Human toxicology of pesticides 9780429266775, 0429266774, 9781000006308, 1000006301, 9781000013122, 100001312X, 9781000019643, 1000019640, 9780367219031

Table of contents :
Content: Introduction. Organophosphorus Compounds. Carbamates. Organochlorine Compounds. Synthetic Pyrethroids. Organotin Compounds. Organomercurial Compounds. Dithiocarbamate Compounds. Benzimidazole Compounds. Chlorphenoxy Compounds. Dipyridiliums. Miscellaneous Pesticides. Combined Exposure. Epidemiology of Acute Intoxications. Reentry Periods.

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Human Toxicology of Pesticides Authors

Fina P. Kaloyanova

Professor Head, Department of Toxicology Research Institute of Hygiene and Occupational Health Medical Academy Sofia, Bulgaria and

Mostafa A. El Batawi Professor Adjunct, University of Pittsburgh Graduate School of Public Health; World Health Organization Consultant Former Director of Occupational Health WHO, Geneva, Switzerland

Boca Raton London New York

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PREFACE The toxicity of pesticides has generated an extensive amount of literature, because of their domestic and public health use, and particular because of their wide use in agriculture, which employs the largest workforce in the world. This book adds new elements and provides for wider needs in the health profession. It has a thorough review of literature on the subject and results of research held in both Eastern and Western countries, which is rare to find in one volume. The literature cited is one of the largest. For each group of chemical compounds used as pesticides, the authors desribe all the known diagnoises and therapies; therefore, this book will be used not only by public health personnel and occupational physicians working in the primary health care systems in rural areas, but also by medical care professionals and research institutions. In several parts of the book the authors refer to the gaps in knowledge that require further research. The chapter on combined effects is expectedly rather short in view of the limited information available on the subject. For more information about combined exposures and effects, the reader may refer to a WHO publication in the Technical Report Series No. 662, in which the mechanisms of response to combined exposure and the variety of effects, e.g., synergism, addition, or independent effects, that may result. The term “TLV” has been widely used throughout the text, because of its familiarity to most of the readers. It denotes a quantitative hygienic standard for a considered safe level expressed as a concentration with a defined average time. It can also be taken to mean maximum allowable concentration, MAC. The authors are fully aware of the WHO program on exposure limits, ELs, which should globally replace TLVs. ELs are internationally recommended and they are based on scientific and epidemiological criteria that are available in the world; they are health based. An occupational exposure limit, OEL, signifies that level of exposure, which in the case of a daily work exposure of 8 hours, will not cause in the individual any disease or disorder from a normal state of health during his working or entire life time or in any of his dependents. This is also fully supported by the ILO. The word “threshold” in TLV is taken in Eastern European countries as the beginning of adverse health effects. Mention of TLV in place of exposure limits was only made for convenience in view of the fact that not many readers are familiar with ELs; however, they generally mean the same thing in practice. It has been internationally agreed that exposure limit is the more accurate term in scientific and health meaning. F. K. and M. ELB.

THE AUTHORS Dr. Fina P. Kaloyanova, M.D., Ph.D., D.Sc., is professor and head of the Department of Toxicology in the Research Institute of Hygiene and Occupational Health, Medical Academy, Sofia, Bulgaria. Dr. Kaloyanova graduated in 1951 to the Medical Faculty in Sofia. In 1961 she obtained her Ph.D. and in 1974 her D.Sc. in the field of pesticide toxicology. She began working as a researcher in 1951, a senior researcher in 1961, and a professor in 1969.From 1972 to 1984 she was the director of the Research Institute of Hygiene and Occupational Health. Dr. Kaloyanova was a president of the Bulgarian Society of Preventive Medicine and now is a member of the board of the National Association of Medical Research Societies. She was vice president of the International Association of Rural Medicine from 1972 to 1975, and a board member of the Permanent Commission and Intematinal Association for Occupational Health from 1972 to 1978. She was elected as a member of the International Academy of Environmental Safety. She has received several Distinguished Service Awards from the Medical Academy, Ministry of Public Health, Bulgarian Government. Dr. Kaloyanova has been a member of the expert panel on occupational health of the World Health Organization since 1972. She participated as a temporary advisor and consultant of more than 50 WHO meetings. She has presented many guest lectures at international and national courses in Egypt, Cuba, China,U.S.S.R, Algeria, Poland, Yugoslavia, and elsewhere. Dr. Kaloyanova has published over 250 research papers and books. Her current major research interests relate to pathogenesis of the pesticide intoxication and determination of the threshold level of the toxic action. Dr. Mostafa A. El Batawi, M.D., D.Sc., is an adjunct professor at the University of Pittsburgh Graduate School of Public Health and a consultant to the World Health Organization, Geneva, Switzerland. Dr. El Batawi received his M.D. in 1951 from Cairo (Egypt) University Faculty of Medicine. In 1957, he earned his Masters of Public Health from the University of Pittsburgh and received his D.Sc. in Occupational Health two years later. From 1957 to 1960 he was a resident in internal medicine, neuropsychiatry, and psychiatry at St. Francis General Hospital, Montifore Hospital, and Western’s Psychiatric Institute and Clinic, University of Pittsburgh, respectively. Dr. El Batawi served as the Chief Medical Officer for the Office of Occupational Health, WHO Headquarters, Geneva, from 1970 to 1988. He has been chairman and professor of the Department of Occupational and Environmental Health Sciences, College of Medicine, New York Institute of Technology. He served as Regional Advisor in Occupational Health for Asia and Western Pacific with the International Labour Organization and the United Nations’ Development Programme and was associate professor and head of the Department of Occupational Health, University of Alexandria, Egypt. Dr. El Batawi has been a member of the International Commission in Occupational Health since 1965 and was a board member from 1981 to 1988. He is a member of the International Epidemiological Association, the American Occupational Medical Association, the American Industrial Hygiene Association, and the Society for Advanced Medical Systems. He is an honorary member of the German Association of Industrial Medicine, the Polish Association for Occupational Medicine, and the International Association for Agricultural Medicine and Rural Health. Dr. El Batawi is also a member of the American College of Preventive Medicine, the Scientific Committee on Occupational Epidemiology of the International Commission on Occupational Health, the New York Academy of Sciences, and the American Human Factors Society.

Dr. El Batawi received the third Theodore F. Hatch Lecture and award from the Graduate School of Public Health, Pittsburgh, and the American Conference of Governmental Industrial Hygienists, as well as the Distinguished Graduate Medallion from the Graduate School of Public Health’s Alumni Association, University of Pittsburgh. He was awarded the Shield of Honor for Serving Humanity in the Fields of Medicine and Health from the Union of Medical Professions, Cairo, Egypt. He has also received the Award of the National Institute for Occupational Safety and Health of the United States for Services to the Health of Working People in the World and the Commander’s Cross for “the best contribution to Occupational Health” from the President of the Republic of Poland.

CONTENTS Chapter 1 Introduction................................................................................................................. 1 Chapter 2 Organophosphorous Com pounds..............................................................................3 I. Introduction................................................................................................... 3 II. Properties....................................................................................................... 3 A. Chemical Structure............................................................................... 3 III. Uses 3 IV. M etabolism.................................................................................................... 3 A. Biotransformation...................................................................................5 B. Biochemical Oxidation.......................................................................... 5 C. Hydrolysis................................................................................................5 V. Toxicity: Mechanism of Action...................................................................5 VI. Exposure: Dose-Effect Relationship.......................................................... 7 A. Occupational Exposure.........................................................................7 VII. Effects on H um ans..................................................................................... 10 A. Acute OP Intoxication..........................................................................10 B. Chronic Intoxications........................................ 12 C. Neurotoxic Effects................................................................................ 14 D. Delayed Neuropathy.............................................................................14 E. Electromyographic Studies.................................................................. 16 F. Central Nervous System .......................................................................17 G. Behavior Changes................................................................................. 18 H. EEG Studies...........................................................................................18 I. Eye and V ision ..................................................................................... 19 J. Long-Term E ffects............................................................................... 19 K. Effect of Individual Compounds on Hum ans.................................... 19 L. Biological Monitoring of OP Exposure..............................................23 1. Exposure Tests as an Early Indication of Health Impairments....................................................................... 24 M. Determination of OP Exposure Indicators........................................ 26 1. Cholinesterase A ctivity.................................................................26 2. OP Metabolites in U rine................................................................28 3. Alkylphosphates in Urine (A P ).................................................... 28 4. OP in Human B lood...................................................................... 29 5. E M G ................................................................................................29 6. N T E .................................................................................................30 N. Other Tests............................................................................................ 30 O. Treatment of Organophosphate Intoxication..................................... 30 VIII. Prevention....................................................................................................31 IX. Conclusion..................................................................................................31 References...................................................................................................34 Chapter 3 Carbamates.................................................................................................................43 I. Introduction.................................................................................................43 II. Properties.....................................................................................................43 III. U se s............................................................................................................. 43 IV. Metabolism..................................................................................................43

V. Toxicity: Mechanism of Action.................................................................44 VI. Exposure: Dose-Effect Relationship........................................................ 46 VII. Effects on H um ans.....................................................................................47 A. Acute Intoxications.............................................................................. 47 B. Volunteer Studies.................................................................................47 C. Occupational Short- and Long-Term Exposure................................48 1. Short-Term Exposure....................................................................48 2. Long-Term Exposure.....................................................................50 D. Biological and Health Indicators of Exposure...................................51 E. Methods Available for ChEA Determination....................................52 F. Treatment of Carbamate Intoxications...............................................53 VIII. Prevention.................................................................................................. 53 IX. Conclusion................................................................................................. 55 References...................................................................................................55 Chapter 4 Organochlorine Compounds................................................................................. 59 I. Introduction............................................................................................... 59 II. Properties................................................................................................... 59 III. U se s............................................................................................................. 59 IV. M etabolism..................................................................................................59 V. Toxicity: Mechanism of Action............................................................... 60 A. Mechanism of A ction.......................................................................... 60 1. Interaction Between Organochlorine Compounds, Drugs, and Hormones....................................................................63 B. Reported Protein-OCP Binding.......................................................... 65 VI. Exposure: Dose-Effect Relationship.......................................................65 A. OCP Levels in Human Tissues........................................................... 66 1. Organochlorine Pesticide Content in Fat T issue........................ 66 2. OCP Content in Different Tissues, Blood, and U rin e................70 B. OCP and Pregnancy............................................................................. 70 C. Human Pathology and Organochlorine Compounds........................ 74 D. Levels of OCP in Workers vs. General Population and Evaluation of their Significance..................................................75 VII. Effects on H um ans................................................................................... 77 A. Acute Intoxications with O C P s.......................................................... 77 B. Chronic Effects of O C P....................................................................... 78 1. Effects of Individual Compounds................................................ 82 2. Cyclodiene Compounds.................................................................86 3. Treatment........................................................................................ 89 4. Prevention....................................................................................... 90 VIII. Conclusion................................................................................................. 90 References...................................................................................................92 Chapter 5

Synthetic Pyrethroids............................................................................................101 I. Introduction...............................................................................................101 II. Properties................................................................................................... 101 III. U se s............................................................................................................101 IV. Metabolism................................................................................................ 101 V. Toxicity: Mechanism of Action............................................................... 102 VI. Exposure: Dose-Effect Relationship...................................................... 104

VII. VIII. IX.

Effects on H um ans..................................................................................105 Prevention.................................................................................................107 Conclusion................................................................................................108 References................................................................................................. 108

Chapter 6 Organotin Compounds............................................................................................I l l I. Introduction...............................................................................................I l l II. Properties................................................................................................... I l l III. U se s............................................................................................................I l l IV. Metabolism................................................................................................111 V. Toxicity: Mechanism of Action..............................................................I l l VI. Exposure: Dose-Effect Relationship...................................................... 112 VII. Effects on H um ans................................................................................... 113 A. Dermal Contact................................................................................... 113 B. Inhalatory Exposure............................................................................114 C. Oral Exposure..................................................................................... 114 VIII. Treatment................................................................................................... 114 IX. Prevention.................................................................................................114 X. Conclusion................................................................................................115 References.................................................................................................115 Chapter 7 Organomercurial Com pounds............................................................................... 117 I. Introduction...............................................................................................117 II. Properties................................................................................................... 117 III. U se s............................................................................................................117 IV. M etabolism................................................................................................117 V. Toxicity: Mechanism of Action...............................................................117 VI. Exposure: Dose-Effect Relationship...................................................... 118 VII. Effects on H um ans................................................................................... 119 VIII. Treatment................................................................................................... 121 IX. Prevention.................................................................................................121 X. Conclusion................................................................................................122 References................................................................................................. 122 Chapter 8 Dithiocarbamate Compounds.................................................................................125 I. Introduction...............................................................................................125 II. Properties................................................................................................... 125 III. U se s............................................................................................................125 IV. Metabolism................................................................................................125 V. Toxicity: Mechanism of action...............................................................125 VI. Exposure: Dose-effect relationship....................................................... 125 VII. Effects on hum ans.................................................................................... 127 VIII. Prevention.................................................................................................. 128 IX. Conclusion................................................................................................128 References.................................................................................................129 Chapter 9 Benzimidazole Compounds....................................................................................131 I. Introduction...............................................................................................131 II. Properties................................................................................................... 131 III. U se s............................................................................................................131

IV. V. VI. VII. VIII. IX.

M etabolism................................................................................................131 Toxicity: Mechanism of Action................................................................ 131 Exposure: Dose-Effect Relationship...................................................... 131 Effects on H um ans................................................................................... 132 Prevention..................................................................................................133 Conclusion.................................................................................................133 References................................................................................................. 133

Chapter 10 Chlorphenoxy Compounds.................................................................................. 135 I. Introduction...............................................................................................135 II. Properties................................................................................................... 135 A. Chemical Structure.............................................................................135 B. Physical Properties.............................................................................135 III. U se s............................................................................................................135 IV. M etabolism................................................................................................ 135 V. Toxicity: Mechanism of Action............................................................... 137 VI. Exposure: Dose-Effect Relationship...................................................... 137 VII. Effects on H um ans................................................................................... 139 A. Acute Inhalation and Dermal E xposure...........................................139 B. Acute Oral Intoxication..................................................................... 140 C. Short- and Long-Term Occupational E xposure.............................. 140 1. Irritative and Allergic Effects: Porphyria Cutanea Tarda....... 140 2. Gastrointestinal System ............................................................... 141 3. Nervous System............................................................................141 4. Psychological E ffects.................................................................. 141 5. Hepatotoxic Effects..................................................................... 141 6. Myotoxic E ffects..........................................................................141 7. Cardiopathy and Cardiovascular Effects................................... 142 8. Endocrine E ffects.........................................................................142 9. Hematological and Biochemical Effects................................... 142 10. Long-Term E ffects.......................................................................142 D. Exposure/Effect Relationship............................................................143 VIII. Safe levels................................................................................................. 143 IX. Conclusion................................................................................................144 References................................................................................................. 145 Chapter 11 Dipyridiliums 147 I. Introduction..............................................................................................147 II. Properties..................................................................................................147 III. U se s............................................................................................................147 IV. M etabolism................................................................................................148 V. Toxicity: Mechanism ofAction................................................................ 148 VI. Exposure: Dose-Effect Relationship...................................................... 148 VII. Effects on H um ans................................................................................... 149 A. Oral Intoxication................................................................................. 150 B. Lung D am age..................................................................................... 150 C. Kidney, Liver, and Gastrointestinal System D am age.................... 152 D. Occupational Intoxications................................................................ 153 E. Dermal Absorption.............................................................................153 F. Local Skin and Nail E ffect................................................................ 153 G. Paraquat Concentrations in Biological M edia................................. 154

H. Treatment of Intoxication.................................................................. 155 I. Recovery after Treatmentof Intoxication.........................................156 VIII. Prevention.................................................................................................156 A. S afeL avels........................................................................................ 156 IX. Conclusion................................................................................................156 References................................................................................................. 157 Chapter 12 Miscellaneous Pesticides...................................................................................... 159 References................................................................................................. 160 Chapter 13 Combined Exposure..............................................................................................161 I. Introduction..............................................................................................161 II. Respiratory System................................................................................... 162 III. Liver and K idneys.................................................................................... 163 IV. Immunotoxicity.........................................................................................164 A. Allergy to Pesticides...........................................................................164 B. Immunosuppression............................................................................165 C. Hematological Changes..................................................................... 166 D. Nervous System .................................................................................. 166 E. V ision.................................................................................................. 167 V. Long-Term E ffects................................................................................... 168 VI. Conclusion................................................................................................. 168 References................................................................................................. 170 Chapter 14 Epidemiology of the Acute PesticideIntoxication.............................................. 173 Conclusion................................................................................................. 177 References ................................................................................................. 179 Chapter 15 Reentry P eriods..................................................................................................... 181 I. Definition of Problem.............................. 181 II. Methodology for Establishment of Reentry Intervals...........................182 III. Studies on Individual Pesticides.............................................................. 183 IV. Reentry Intervals for Some Pesticides.................................................... 184 V. The Problem of Practical Useof Reentry Intervals................................ 184 VI. Conclusion................................................................................................. 185 References................................................................................................. 186 Index

189

Chapter 1

INTRODUCTION Many years before our era, different natural substances were used as pesticides. Later, salts of metals, sulfur, natural oils, and tobacco products were applied. During the last 50 years chemical synthesis of pesticides has increased considerably, and nowadays there are more than 55 classes and 1500 individual substances produced in more than 100,000 formulations. According to the definition of the FAO International Code of Conduct on the Distribution and Use of Pesticides, a “pesticide is any substance or mixture of substances intended for preventing, destroying or controlling any pest, including vectors of human or animal disease, unwanted species of plants or animals causing harm during or otherwise interfering with production, processing, storage, transport or marketing of food, agricultural commodities, wood and wooden products or animal feedstuffs, or which may be administered to animals for the control of insects, arachnids or other pests in or on their bodies. The term includes substances intended for use as a plant-growth regulator, defoliant, dessicant, or fruit tinning agent for preventing of premature fall of fruit and substances applied to crops either before or after harvest to protect the commodity from deterioration during storage and transport.” According to their target, pesticides are divided into several main groups: 1. 2.

Insecticides Other insect-control agents Chemosterilants Pheromons (sex attractants and synthetic lures) Repellents Insect hormones and hormone mimics (insect growth regulators) 3. Specific acaricides 4. Protectant fungicides 5. Eradicant fungicides (chemotherapeutants) 6. Soil fumigants and nematocides 7. Herbicides 8. Dessicants, defoliants, and haulm killers 9. Rodenticides 10. Plant growth regulators 11. Molluscicides The specific conditions of pesticide application in agriculture, forestry, industry, public health, and households make them one of the most common type of chemicals coming into contact with all groups of a population. They have gained a widespread use in all countries due to their proven effect in vector control and their high effectiveness in agriculture. However, pesticides represent a very serious health and environmental problem; preventing their eventual adverse effects is much more difficult than is the case with other substances used in industry. Pesticide application mainly requires scattering onto large areas (millions of hectares of soil) and using concentrations capable of killing selected plant and animal species. It is evident that the protective measures for both workers and useful animal species are very limited and specific. Their circulation in the environment cannot be brought under control. Therefore, public and occupational circles are greatly concerned with coping with the present and eventual unknown future and the delayed adverse effects of pesticides that represent a hazard for human progeny and the environment. The hopes are set on integrated pest management.

1

2

Human Toxicology of Pesticides

The present book only concerns itself with the adverse effects pesticides have on human health. The book attempts to evaluate the available literature data, as well as the authors’ own investigations on the human toxicology of pesticides. The data on some groups of compounds are very poor, on others nonexistent. We hope the book will be useful, not only to physicians, but to specialists in different fields who are interested in the problems related to pesticides.

Chapter 2

ORGANOPHOSPHOROUS COMPOUNDS I. INTRODUCTION The largest group of pesticides used nowadays is the group of organophosphorous compounds (OP). More than 100 individual compounds of this group are well known and largely used in many countries. OP degradation in the environment, compared with organochlorine pesticides (OCP), is very fast. Their stability in the environmental media is calculated in months; OCPs persist for years in the environment. In many cases, OP pesticides were a good alternative to previous application of OCPs, especially DDT and hexachloran, as well as, to some extent, some pesticides from the cyclodien group. A disadvantage of OP pesticides is their high acute toxicity and the resulting large number of fatal acute intoxications. Synthesis of OP compounds is still in progress, and substances with more specific or selective effects have been synthesized. At the same time, they are less toxic for higher organisms, including man.

II. PROPERTIES A. CHEMICAL STRUCTURE Table 1 presents the general chemical structures of the principal OP groups together with the common or other pesticide names from each group. An extensive list of OPs with trade names is given in WHO EHC No 63,1where molecular weight, CAS registry number and CAS chemical name are given as well. Molecular weight of OPs varies from 183 to 466. They are formulated as water soluble powder, liquid concentrate, or granules. All are rapidly hydrolyzed and oxydized, in the environment and in alkali media, to mono- or disubstituted phosphoric or phosphonic acid or their thioanalogs. Some isomerization reactions occur while storing OPs at high temperatures, and more toxic derivatives are formed. Humidity and sunlight also play a role in the transformation of OPs under natural conditions. Degradation in the environment involves both hydrolysis and oxidation to water soluble products. Microbial degradation also contributes to the fast disappearance of OPs from the treated fields.

III. USES OPs are the most used group of pesticides worldwide in view of their efficiency and rapid degradation in the environment and living organisms. Most are insecticides, but some are used as fungicides, herbicides, and raticides. They are used in agriculture and forestry and for public health purposes as a 0.02 to 0.08% water solution for spraying, 2.5 to 8% as aerosols and 4% as dust.2

IV. METABOLISM OPs enter the body through the nose, skin, or mouth. Uptake through the skin may be very extensive for OPs, since more of them are lipophillic. Percutaneous penetration of man by parathion and malathion labeled with radioactive carbon was studied by Maibach and Feldmann.3 Pesticides were applied on different anatomic regions of volunteers. As a criterion for absorption, urinary recovery of 14C was studied. The scrotum allowed almost total absorption of 3

4

Human Toxicology of Pesticides TABLE 1 General Chemical Structure and Common or Other Names of Ogranophosphorous Insecticudes Type of phosphorus group

Outline structure

Common or other names

Phosphate

Chlorfenvinphos, crotoxyphos, dichlorphos, dicrotophos, heptenphos, mevinphos, monocrotophos, naled, phosphamidon, TEPP, tetrachlorvinphos, triazophos

O-alkyl phosphorothio

Amiton, demeton-S-methyl, omethoate, oxydemetopmethyl, phoxim, vamidothion Axothoate, bromophos, bromophos-ethyl, chlorpyriphos,chlorpyriphos-methyl, coumaphos, diazinon, dichlofenthion, fenchlorphos, fenitrothion, fenthion, fensulphothion, iodofenphos, parathion, parathion-methyl, phoxim, pyrasophos, pirimiphos-methyl, sulfotep, temephos, thionazin

Phosphorodithioate

Amidithion, azinophos-ethyl, azinophosmethyl, dimetoate, dioxathion, disulfoton, ethion, formothion, malathion, mecarbam, menazone, methidathion, morphothion, phentoate, phorate, phosalon, phosmet, prothoate, thimeton

S-alkyl phosphorothioa

Profenofos, trifenofos

S-alkyl phosphorodithk

Prothiofos, sulprofos

Phosphoramidate

Cruformate, fenamifos, fosthietan

Phosphorotriamidate

Triamifos

Phosphorothioamidate

Methamidofos (tamaron)

Isofenfos

Organophosphorous Compounds

5

TABLE 1 (continued) General Chemical Structure and Common or Other Names of Ogranophosphorous Insecticudes Type of phosphorus group

Outline structure

Common or other names

Phosphonate

Butonate, trichlorfon (tribyton)

Phosphonothioate

EPN, Trichlormat, leptophos, cyanofenphos

parathion, axilla — 63%, ear canal — 46%, forehand — 36%, scalp — 32%, foot— 14%, palm — 11%, forearm — 8.6%. Malathion penetration was lower. A. BIOTRANSFORMATION The three main reactions for OP biotransformation are biochemical oxidation, hydrolysis, and transferase reaction. B. BIOCHEMICAL OXIDATION Mixed function oxidases (MFO) are involved in this process. Many OPs can be oxidized by MFOs in liver endoplasmic reticulum, but also by MFOs found in the intestines, kidney, and lung. Oxidative desulfuration of P=S groups to P=0 almost always leads to more toxic products. Phosphorothioate activates to phosphate, a direct ChE inhibitor. Oxones are less lipophilic and more rapidly hydrolyzed. This reduces their accumulation in the body. Other reactions mediated by MFOs are oxidative N-dealkylation, oxidative O-dealkylation, oxidative dearylation, thioeter oxidation, and side-chain oxidation. C. HYDROLYSIS In OP hydrolysis, some hydrolytic enzymes are involved. Commonly known among them are A-esterases or phosphoryl phosphatases. Some authors call them in accordance with the OP compound used as a substrate — “paraoxonase”, “malaoxonase”, etc. Georgiev has recently given a scheme for the biotransformation of OPs (Figure l).5

V. TOXICITY: MECHANISM OF ACTION OPs show identical toxic effects, mainly due to the cholinesterase inhibition. Three main biochemical reactions are responsible for the effect of OPs.67 1. 2. 3.

Inhibition of cholinesterase activity Inhibition of neuropathy target esterase (NTE) and development of delayed neuropathy Release of alkyl groups attached to the phosphorous atom and alkylation of macromolecules including RNA and DNA

The principal mechanism of OP action is inhibition of cholinesterase activity (ChE A), the enzyme performing the hydrolysis of acetylcholine to choline and acetic acid. Specific ChE(acetylcholinesterase 3.1.1.7) is located in the nervous ganglionic synapses of neuromus-

6

Human Toxicology of Pesticides-

FIGURE 1. The general scheme for the main metabolite process of OPs (adapted by Georgiev5).

cular structures and in erythrocytes. Nonspecific ChE(3.1.1.8) is found mainly in the plasma and liver. Organophosphorous insecticides generally inhibit both enzymes. With the change of the membrane potential, acetylcholine (ACh) acts as a mediator of the nerve impulse. In the cytoplasm of the nerve end, before the synaptic membrane, special vesicles contain acetylcholine, which is synthesized by the enzyme cholinacetylase (ChA) from acetyl CoA and choline. The nerve impulse produces a discharge of ACh across the synaptic gap. The ACh contacts cholinergic receptor protein molecules of the postsynaptic membrane and changes its configuration, enabling Na and K cations to penetrate. The transfer of the nerve impulse continues. This process is very short, lasting about 1/500 s, and is followed by ChE hydrolysis of ACh. In normal conditions the half-life for the hydrolysis of acetylted ChE is 2.3 x 10‘6 min. The OPs produce phosphorylation of the ChE esteric binding site. The half-life of dimethyl posphorylated ChE hydrolysis is about 50 min, and for diethyl phosphorylated it is about 60 h. Inactivation by ChE phosphorylation stops the hydrolysis of ACh. Excessive quantities of ACh accumulate at peripheral ganglionic and central nerve endings (synapses) in effector organs, elevated concentrations occur in plasma and intestinal fluid. The intoxication effects connected with the excitement of M- and A-choline receptors (present on nerve terminals of effector organs) are as follows: •

•

Muscarine effect due to postganglionic cholinergic nerve impulses exciting the M -choline receptors of the lungs, gastrointestinal system, heart, kidneys, sweat glands, pupils and muscles Nicotinic effect on the receptors of ganglionic synapses and motoric plates, the medular part of glandula subrenalis, and carotic nodules

Organophosphorous Compounds

1

Central effect of ACh due to nerve cells or ACh accumulation directly impacting the choline receptors, with parallel inhibition of other enzymes by OPs such as lipase, cholesterol esterase, proteinase, monoaminooxidase, and other nonspecific esterases The duration of the symptoms depends partly on the rate of ChE reactivation. Spontaneous reactivation depends on the chemical structure of the phosphoryl group attached to the enzyme. The reactivation of the inhibited enzyme can be facilitated considerably by special compounds (oxymes). Several of these compounds have become important antidotes in the treatment of poisoning. The inhibited enzyme may also be transformed into a state where no spontaneous reactivation occurs and where oximes are no longer capable of reactivating it. The phenomenon is called “aging” and is characterized by removal of one of the alkyl groups from the phosphoryl groups attached to the enzymes. The rapidity of inhibited ChE aging depends on the chemical nature of the phosphorylating insecticides.910 OPs inhibit a class of esterases which use serin in their catalytic centre and are called serin esterases or B-esterases.8 This inhibition is not significant for acute toxicity, but it may have other toxicological significance (potentation, detoxication, etc.). The inhibition of neuropathy target esterase (NTE) protein, found in the nervous system, is responsible for the development of dalayed neupathy.11 Delayed neuropathy can only occur for some phosphates and phosphonates — i.e., one of the groups (R, or R2) is attached to the phosphorus atom by oxygen or nitrogen. Phosphonates, in which both R, and R2 are attached directly to the phosphorous atom by P-C bonds, do not cause delayed neuropathy. Although they may be potent inhibitors of neurotoxic esterase, the inhibited enzyme cannot age, and therefore, does not cause delayed neuropathy. Lotti and Johnson performed comparative studies on the distribution of NTE and ChE in brain.12ChEA was greater in the nucleous caudatus, but the NTE was found in almost the entire cortex area as well as in some parts of the cerebellum and the spinal cord. These authors also detected NTE in the femoral nerve — 50 nM/min/g wet weight. The normal values of NTE in the human cortex are 2,390 + 100 nM/min/g wet weight.

VI. EXPOSURE: DOSE-EFFECT RELATIONSHIP If good agricultural practice is followed, the exposure of general population by food is negligible. The only possible serious exposure could occur during OP spraying for public health or for individual oral or local application against some parasitic diseases. Oral dose-effect relationship was studied during treatment of some parasitic diseases and in volunteer studies (Table 2). Dipterex was used to treat schistosomiases in thirty children from 4 to 12 years old, in doses of 5 to 10 mg/kg in relation to age, for 10 d. The inhibition of erythrocyte ChE changed from 19 to 52%, with a mean of 32%. Pseudocholinesterase decreased insignificantly, by maximum 15%. No liver, hematopoetic, or renal impairments were demonstrated.17 Similar results are reported by Beneyt et al.14 They used a dose of 500 mg dipterex to treat adults twice in two consecutive days with no adverse effect. Only ChE was inhibited. Other patients, treated with 1 g daily and 1.3 g daily, suffered to a greater or lesser degree of gastrointestinal pains. The ChE inhibition was considerable, in some cases reaching less than 20% the normal mean level. In this study the inhibition of ChE activity was pronounced. A. OCCUPATIONAL EXPOSURE Occupational exposure to OPs has been the subject of many studies concerned with preventing eventual health impairments. Data concerning exposure concentrations and OP effects are shown in Table 3.

8

Human Toxicology of Pesticides TABLE 2 Oral Dose-Effect Relationship In Some OPs1516 Dose with observed effect in mg/kg/b.w. Name of Pesticide

Dose in mg/kg with no observed effect

Azynophosmethyl

0.2/30 d

Abate

256 mg/man/d 5 d 62 mg/kg/d 4 weeks

Bromophos

0.4/4 weeks

Dichlorophos

0.033/28 d

Dose/term of application

Kind of effect

0.3-0.33 (time undetermined)

ChE inhibition

1/d 3 weeks 8/d 3 weeks

Inhibition of ChE plasma Inhibition of ChE plasma by 70%, gastrointestinal disorders Inhibition of ChE plasma by 90%, inhibition of erythrocyte ChE Inhibition of ChE plasma by 25%, no inhibition of Er ChEA

16/d 5 d 5/d 10-20 d

Demethon 5-methyl 0.5/single

0.4/30 d

ChE inhibition by 20%

Diazinon

0.02/34 d

0.25/43 d 0.05/5 d, repeated after 23 d

Plasma ChE inhibition by 20% Plasma ChE inhibition by 35%

Dimethoate Dioxathin Disulfotan Chloropyriphos Fenchlorophos Formothion Malathion

0.2/57 d 0.075/28 d 0.075/30 d 0.1/1 month 10.7/4 d 0.2/59 d 0.2/88 d

0.5/single

ChE inhibition

19.4/7 d 0.5/59 d 0.4/88 d 0.8/2 weeks

ChE inhibition ChE inhibition ChE inhibition ChE inhibition

Methidathion

0.11/6 weeks

Mevinphos

0.014/30 d

0.025/single

Inhibition of erythrocyte ChE only

7.5/one dose at 2 weeks intervals 7/four time at fortnight intervals 24/single

ChE inhibition nausea Diarhea, abdominal pain, restlessness Tachycardia, abdominal pain, vomiting, tremor, sweating

0.05/3 weeks

0.12/6 weeks

0.06/43 d

0.1/28 d 0.12/27 d

Plasma and erythrocyte ChE inhibition by 35% Plasma ChE inhibition by 15%

Phenitrothion

0.04-0.08 x 24 h intervals

0.3/single dose

Phenthion

0.02/single

Pyrimiphosmethyl

0.25/28 d

Trichlorfon

Parathion

ChE inhibition

Organophosphorous Compounds

9

TABLE 3 Occupational Exposure to OP Concentration-Effect Relationship Pesticides

Concentration (mg/m3)

Symptoms

Dichlorphos15

8/21 d 1/21 d 0.033/28 d 6.9/30 to 60 min 0.9 to 3.5/8 h 0.25/11 weeks, 4 d a week 0.51/single

Mild symptoms ChE inhibition No effects No symptoms and no ChE inhibition Slight ChE inhibition No changes Slight reduction of ChE; tolerated dose received by inhalation is about 0.5 mg/man/d, 1 mg/man/d produced slight plasma ChE reduction

Bromophos15

During spraying for 14 d

Slight reduction of ChE max by 25% — reactivation in a month

Fenitrothion15

One week spraying

Inhibition of blood ChE by 50% in some of the sprayers

Shradan18

0.1-3 0.03-0.9 (duration of exposure not specified)

Blood ChE inhibition, constriction of pupils Burning eyes, headache, weakness

Malathion19

0.1-3 long-term exposure

Inhibition of ChE in 1/2 of the workers, decrease of albumin and beta and gama globulines

Parathion20

0.1-0.8/short-term exposure 6-13/short-term exposure

ChE reduction Acute intoxication

DDVP21

0.8-3/1 d

ChE inhibition by 19-23%, no symptoms

Trichlorphor20

0.010-0.034/short-term spray operators

No changes

Phosfolan23

0.008-0.3% toxic dose

Inhibition of erythrocyte ChE by 31—44%; partial recovery in 48 h, full recovery in 3^1 weeks

Dipterex24

1.54, 0.38, 0.52 long-term exposure in formulation plant

Inhibition of blood ChE, EEG changes

Wolfe et al. studied the magnitude of potential dose to be absorbed during exposure to the air blasted in power drawn tractors.25 Values for potential dermal and respiratory exposure, and for total exposure in terms of fractions of toxic dose, were determined for different pesticides during orchard spraying. The highest total exposure was calculated to be only 1.12% of the toxic dose/ h for workers applying the OP compound carbophenothion, the most toxic compound in the study. In another study, an orchard exposed to parathion was calculated to be 19 mg/h dermal and 0.02 mg/h inhalatory2. In practical conditions workers wear the required protective gear, which considerably reduces the chemical absorption. Wolfe et al. calculated potential parathion exposure in a parathion formulating plant based on minimum protective means (without respirator or gloves and with short sleeves).26 The mean dermal exposure for 11 workers was 67.3 mg/h, and the mean respiratory level was 0.62 mg/h; this represents 5% of the toxic dose per h. The highest values obtained during the test period were 335 mg/h dermal and 3.4 mg/h respiratory exposure, equal to 25% of the toxic dose. Such an exposure represents a big hazard. Cavanga et al. and Cavanga and Vigliani studied the effects of vapona strips in a hospital. They determined the ChEA in persons exposed to different vapona concentrations in the air for about 11 d. In 66 patients they only found inhibition of plasma ChEA levels ranging from 35 to 72% (average 54%) when exposure concentrations were 0.1 to 0.28 mg/m3. No changes were found at concentrations of 0.02 to 0.1 mg/m3, except for patients with liver disease. The authors

10

Human Toxicology of Pesticides TABLE 4 Potential Route of Intoxication by Demethon and Parathion29 Route of absorption

%

Dermal Inhalatory Oral Miscellaneous

71 8 11 10

calculated the intake of vapona, assuming complete absorption and air 10 m3/d inhaled air in adults and children. They found that 1.73 mg vapona daily is the average absorption in adults, which provokes 54% inhibition of ChE, 0.34 mg/daily for liver patients — 44% inhibition, and 0.2 mg/daily for children — 25% inhibition. No symptoms were recorded. A study by Shih et al. suggested that a percutaneous route of entry was the dominant one among sprayers.29 They analyzed the reasons for parathion and demethon intoxications in an area of China and found 71% to be related to dermal absorption (no protective gloves, contaminated clothes, unclothed arms and legs, leaky tools, and spraying against the wind). The distribution of the intoxications by route of absorption is shown in Table 4. Direct evidence for their conclusion are the low concentrations measured in the breathing zone (0.02 mg/m3 in only one of the samples) and the high amount of parathion contamination on the skin, e.g., arm (30^m2) — 5.7 mg, glove or right hand — 1.271 mg, and leg (30cm2) — 30.8 mg. Dermal absorption has been proved to be the primary route of malathion intake during spraying and mixing operations.30The average daily dermal exposure has been 330 mg and the absorbed dose was calculated to have been 26 mg daily. Respiratory exposure to airbom malathion was extremely low (mean 0.43 mg/m3 and peak 1.54 mg/m3). Pesticide spraying has been shown to deposit on exposed surface 20 to 1700 times more than the amount reaching the respiratory tract .31 Davies et al. undertook a study to determine the potential dermal and respiratory exposures experienced apple thinners received while working in orchards 24 and 48 h after the first seasonal cover spray of phosalone.32The total foliar residues found in the study were 2.1 pg/cm2 on both days. The potential dermal and respiratory exposure were reported to be, respectively, 9.0 and 0.13 mg/h at 24 h and 7.1 and 0.081 mg/h at 48 h. The thinners were assumed to have received 0.034% of a lethal dose by the dermal route and 0.0015% of the lethal dose/h by the respiratory route. While working their normal 7.5 h a day, they would receive a total of 0.27% of the lethal dose. Farmers planting com and applying granulated terbufos as a soil insecticide and nematocide were estimated to have dermal exposure ranging from 5 to 156 pg/h, with an average of 72.4 pg/ h, and respiratory exposure ranging from 2.8 to 27.4 pg/h, with an average of 11 pg/h. The estimated percent of toxic doses calculated ranged from 0.01 to 0.20 with an average of 0.111. No detectable absorption of terbufos was found in the farmers, as indicated by the results of the urinary alkyl phosphate analyses and cholinesterase measurements. The conception, based on these results, is that the granular form of terbufos does not present a significant hazard. It should be mentioned that the acute LD50 of the active ingredient is 1.1 mg/kg by dermal application.33

VII. EFFECTS ON HUMANS A. ACUTE OP INTOXICATION The number of accidental and occupational poisonings from OP compounds seems to correlate well with their absolute toxicity. According to Namba, during a seven year period in Japan there were 63 cases of malathion intoxication, including 10 deaths, and 3311 cases of parathion intoxication, including 188 deaths.32The relatively low potential hazard of malathion

Organophosphorous Compounds

11

TABLE 5 OP Acute Intoxication Symptoms And Signs (Adapted)9 Site of action

Signs and symptoms

Eyes

Increased lacrimation, slight myosis (occasionally unequal, later marked), blurred vision, eye pain when focusing, frontal headache, conjunctive hyperemia

Respiratory system

Rhinorrhea, hyperemia (local exposure), tightness in chest, prolonged wheezing, bronchoconstriction, increased secretion, dispnea, slight chest pain, cough, edema of the lung

Gastrointestinal system

Increased salivation, anorexia, vomiting, abdominal cramps, epigastric and substemal tightness (cardiospasm) with “heartburn” and eructation, diarrhea, tenesmus, involuntary defecation

Sweat glands

Increased sweating

Striated muscles

Easy fatigue, mild weakness, twitching, fasciculations (more pronounced at the side of exposure to the liquid), cramps, generalized weakness including respiratory muscles, dispnea, cyanosis

Central nervous system

Giddiness, tension, anxiety, tremor, restlessness, emotional lability, excessive dreaming, insomnia, nightmares, headache, tremor, apathy, withdrawal and depression, slow wave bursts of elevated voltage in EEG (especially on hyperventilation), drowsiness, concentration difficulty, slow recall, confusion, slurred speech, ataxia, generalized weakness, coma with absence of reflexes, Cheyne-Stokes respiration, convulsions, respiratory and circulatory centers depression, dispnea, cyanosis, fall in blood pressure

Circulatory system

Bradycardia, decreased cardiac output, cardiac arrest, vasomotor center paralysis

to humans is related to its lower toxicity: LD50dermal >4000 mg/kg and the estimated lethal oral dose for a 70 kg man is 60 g, compared to 6.8 to 21.0 mg/kg dermal LD50for parathion and lethal oral dose of 0.1 g. This is not the case if malathion is mixed with maloxon.30 As it was mentioned before, compounds containing a P=S nucleus, such as parathion, malathion, etc., must be activated by the metabolic change of S by O, which is performed by mixed function oxidases of the liver and intestinal wall. Such compounds are called indirect inhibitors of cholinesterase activity. Symptoms of OP intoxication are given in Table 5. Death is due to asphyxia in some instances and to cardiovascular failure in others. In many cases only a few of these symptoms are observed. The interval between exposure and onset of the symptoms may be as short as a few minutes but is usually 1 to 2 h. In cases with predominantly percutaneous intake, this interval is prolonged. Thess et al. report a case of clinically unrecognized, protracted poisoning that started 6 h after the working day of a tractor sprayer ended; he had handled wofatox-concentration 50 and wofatox-spraying solution.33 Rarely the interval exceeds 24 h. Other symptoms, such as fever, are also reported, but they are atypical. The respiratory failure results from a combination of respiratory tract blockage from excessive secretion of the salivary glands and respiratory tract, possible bronchoconstriction, and paralysis of the respiration area of the brain stem. According to Zakurdaev the toxic myopathy, e.g., paresis and paralysis of the respiratory muscles, leads to the development of respiratory failure in 5 to 7 d after a severe intoxication.34 Organophosphorous compounds generally have been considered little or no cause of primary irritation. Accordingly, relatively few records on the occurrence of skin lesions related to these pesticides are kept. However, the Matsushita et al. survey found that, of all the patients affected by pesticides, the incidence rate of contact dermatitis provoked by OP compounds was 36.5%.64 From the case analysis, causative OP compounds were found to be DDVP, salithion, simithion (fenitrothion), phosvel, cyanox, kilval, diazinon, and malathion.

12

Human Toxicology of Pesticides

The OP effects on the immunological reactions, which may influence morbidity, are very important. Milby and Epstein found that agricultural workers exposed to malathion were sensitized to the intermidiary product diethyl fumarate, and when this compound was decreased in the manufactured product, the incidence of subsequent sensitization also decreased.65 Allergic effects due to exposure to OP compounds are described. Nevertheless, Ganelin et al., Davignon et al., and Gardner and Iverson believe that for asthmatic patients such exposure should not be considered an additional risk of increased bronchial sensitivity.66'68 Unless exposure causes death, most neurological effects are reversible dependent on ChE inhibitors. Local and less severe effects do not usually last more than one day. Myosis also disappears in less than 1 week, and most other symptoms diminish over the next 6 to 18 d. The symptoms of the intoxication are related to the rate of ChE inhibition and the rate at which the inhibitor itself is destroyed or removed from the tissue. Both these factors are related to the chemical structure of the compounds and eventual presence of byproducts. Diagnosis of the intoxication can be difficult in mild cases, when only myosis, nausea, vomiting, weakness, headache, and giddiness are observed. In such cases a good anamnesis and ChEA determination will help very much. Unusual toxicological features in poisoning by fatsoluble OPs are reported by Davies et al.4 In 5 suicidal patients who used dichlorfenthion, the initial symptoms were mild, and cholinergic crisis appeared at 40 to 48 h after ingestion. Two patients died and in the other three ChE inhibition persisted for 48 d. In one patient almost total inhibition of both plasma and erythrocyte ChE was noted for 66 d. This corresponded to pesticide presence in fat tissue at the 54th d and in blood at the 75th d. The levels of dichlorfenthion in adipose tissues in this case were, respectively, 65, 58, and 0.63 ppm on d 4, 7, and 54 after poisoning. Leptophos is more fat soluble and produces a more protracted clinical picture. In household situations, OP compounds provoke mostly severe acute intoxications. Such intoxications are described by Golden et al., Favre, Gervais et al., Gupta and Patel, Tefik, Bledsoe and Seymour, Cattle.35'41 The acute cases are almost always severe, often with lethal issue. The possibilities of a successful treatment increase with the reactivation of cholinesterase, when the patients are duly hospitalized. Gaultier et al. reported a case with an intake of 800 mg parathion.42 The treatment was successful with methyl-a-pyridinaldoxim, atropin, and reanimation administered successively. The late diagnosis as well as complications with pneumonia, sepsis, etc. raised serious problems in the treatment.43 In spite of the intensive therapy, 12.7% of the patients with poisoning by OP compounds die from heart and lung insufficiency.44 Tabershaw and Copper investigated the consequences of acute poisonings with OP compounds.45 A group of 114 subjects poisoned before 3 or more years were investigated; 6 of them had had severe intoxication, 54 moderate poisoning, and 54 light poisoning. Of the group 43 had complaints 6 months after the accident, and in 13 the complaints persisted up to the moment of the examination. Gastrointestinal complaints, eye and brain disturbances, cardiorespiratory, neuropsychic, and other effects were registered. In 8 subjects eye disturbances were found, including longsightedness in 4 of them. Intolerance toward the odor of pesticides manifested in 20 of the subjects with such symptoms as nausea, vomiting, headache, etc. Plasma ChEA was increased. West published the results of a follow-up study on the sequelae of poisonings with OP pesticides.46 She found that one fourth of the subjects intoxicated had complaints six months up to several years after the accident. The nervous symptoms were attributed to cerebral anoxia. B. CHRONIC INTOXICATIONS Chronic intoxications are rare, because OPs are not highly cumulative. The same symptoms as in acute intoxications are found but are less pronounced: headache, giddiness, insomnia, weakness, increased sweating, nausea, loss of appetite, tremor, and nystagmus.

Organophosphorous Compounds

13

In epidemiological studies, most frequently reported are liver, renal, skin, cardiovascular, hemopoetic, and respiratory disturbances, as well as aggravation of existing ill health conditions. The literature data on chronic OP effects are difficult to evaluate because of the interference other toxic substances have during production or other pesticides have during application. Hartwell and Hayes reported observations on workers in two plants that produce phosdrin, methylparathion, and ethylparathion.47 The ChEA inhibition has been a frequent finding; however, clinical syndroms appeared very seldom. From 41 cases with inhibited ChEA, 17 have shown different symptoms of intoxication. Faerman traced the conditions of 179 persons employed in an OP compound production plant: mercaptophos — 50 subjects, chlorophos — 49, methylethylphos— 48 and metaphos — 32.48 OP concentrations in the air of the working rooms exceeded two to three times the MAC values. A possibility for skin resorbtion existed, as well. The ECG has shown bradycardia and sinus arythmia. According to the author, the ECG and oscillographic studies suggested the presence of an increased vagus tonus. Neurologically, a vegetative dystonia was found, demonstrated by a red dermographism, acrocyanosis, and positive orthostatic reflex, which the author related to the toxic effect of OP compounds. Gastrointestinal tract dyspeptic phenomena were also registered. The functional state of liver showed disturbed proteinsynthesis and hydrocarbon function (elevated blood sugar content, significantly higher 0Cj and a 2-globulins together with decreased albumin quantity and a lower albuminoglobulin ratio). At fractional investigation of stomach content, secretory disturbances, such as increased or decreased acidity up to full achylia, were found. Similar changes were reported by the same author some years later. Kudo investigated 182 agricultural workers engaged in OP application.49 In 63.9% of them, the pesticide content in blood was 0.004 to 0.520 mg/kg, with a mean of 0.01 mg/kg. Chronic intoxication was diagnosed in 14 workers. LDH, LAP, and aldolase activity in blood serum were significantly below the normal values, especially working with methylparathion. Ophthalmological impairments were observed in two workers. Pyramidal and extrapyramidal damage and cerebral ataxia were also found, as well as deep injuries in the sensory system and parasympaticus (hyperactivity, manifested by myosis and hyperemia of the face). Women working in rice and barley fields, and exposed to OP pesticides, averaged a 5 to 10 kg decrease in body weight, menstrual disturbances, amenorea, and sterility (mainly transient).50 Changes in some biochemical parameters, such as an increased amino acid levels and higher total serum protein have been attributed to the liver function disturbances. There were changes in the albumin globulin index, the serum enzyme activities of aldolase, the alkaline phosphatase, SGOT, SGPT, asparagin amino transferase, and omitincarbamyl transferase as well.51'56 Exposure to OP compounds leads to increased histidine and valin content in the blood and a tendency toward increased cystin, lysin, arginine, alanine, and others.53 Decreased reabsorption of phosphorus, due to impaired renal function, has been observed. Urinary amino acid studies demonstrated increased excretion of arginine, omitine, and lysin.57'59 Functional effects on the cardiovascular system such as bradicardia, hypotension, and electrocardiographic changes have been established by other authors.60,61 Intestinal disturbances such as hypoacidity or achylia and occasional acidity are also reported. Parathion was supposed to produce aplastic anemia.62 During chronic exposure leukopenia is reported often, mainly when combined exposure takes place.63 Edmundson and Davis found that the active ingredient in naled formulations was the primary sensitizing agent, and its hydrolytic products caused no such reaction.69 Ercegovich published a review on pesticide immunological interactions.70He concluded that sensitization to high doses of pesticides, as evidenced by dermatitis, may be more prevalent than previously supposed. However, there is no sufficient information to confirm that exposure to

14

Human Toxicology of Pesticides

low doses of pesticides is actually responsible for hypersensitivity. Several groups produced antisera responsive to protein conjugates of parathion and malathion. On the basis of the information presently available, OP pesticides are not a serious threat to the immunological defense system of human body. Abnormal exposure to these agents undoubtedly induces hypersensitivity reactions, primarily of the nature of cutaneous manifestations, but there is no evidence that they readily alter the defense mechanism of the body. C. NEUROTOXIC EFFECTS The neurotoxic effects from OP insecticide exposure can be classified as either directly related to ChE inhibition or delayed neurotoxic actions. Most OP poisoning effects are directly related to ChE A inhibition. The mechanism of toxicity involves the inhibition of ChEA at cholinergic nerve synapses with the resulting accumulation of acetylcholine. Prolonged cholinergic stimulation may create a muscle necrotizing effect. Some reported cases with flaccid paralysis and rapid recovery are related to the cholinergic effect but not to neuropathy (malathion, omethoate, parathion, merphos).1 This effect is dose dependent. A critical inhibition of AChE activity is by 85%. Pathological changes are initiated at the motor endplates over a period of 2 h and by the 24th h a generalized breakdown of muscle fiber structure is evident. D. DELAYED NEUROPATHY OP-induced delayed neuropathy (OPIDN) is a syndrome, caused by some, but not all, esters. It is characterized by a delayed manifestation of the clinical effects, one to three weeks after the beginning of the intoxication. It is called peripheral distal axonopathy. The resulting paralysis is caused by concurrent degeneration of the distal regions of long, large diameter axons in the peripheral nerves and spinal cord.71,72 Johnson first associated the delayed neurotoxic effects, attributed to the OP insecticides, with the inhibition of the so called neuropathy target esterase (NTE).11It is presumed that the process initiates by covalent phosphorylation of the active center of NTE. Aging of the inhibited NTE (Figure 1) is suggested, but still unproven with all the neuropathic agents, to be the second essential step in the inhibition process.73 According to Johnson, after the interaction with an OP, the protein called NTE may exist in three forms.74 The total of these three forms (T-NTE) could be expressed by the following equation: (T-NTE) = (Ca-NTE) + (UI-NTE) + (MI-NTE) where Ca-NTE is catalytically active, UI-NTE is unmodified inhibited, and MI-NTE is modified inhibited. The modification involves a bond cleavage and the generation of a negative charge. Extensive research concluded that initiation of OPIDP depends on the generation of a substantial amount of MI-NTE. The substances commonly causing delayed neuropathy in man are triaryl phosphate esters used in hydraulic fluids; they have no AChE activity and they are not pesticides. Table 6 lists the OP pesticides for which reasonable evidence exists that they have caused delayed neuropathy in man.1 Predominant motor paralysis affecting the distal muscles of the limbs, minimum sensory abnormalities, and calf pain preceding the onset of weakness are typical for polyneuropathy caused by OP compounds. The electrophysiological findings of partial denervation, with the surviving fibers conducting at normal rates and the pyramidal tract signs noted during the late stages of the illness, are also typical.75 In a study by Lotti et al. on workers occupationally exposed to the organophosphorous defoliants IDEF and merphos for several weeks, no abnormalities were found, and there were

Organophosphorous Compounds

15

TABLE 6 Organophosphorous Pesticides Reported to Cause Delayed Neuropathy in Man1 Pesticide

Number of cases

Mipaphox Leptophos

2 8

Methamidophos Trichlorphon

9 many

Trichlomat EPN Chlorpyriphos

2

3 a

1

Reference Bidstrup et al.77 Xintaras et al.,83 FAO/WHO,84 Murphy78 Senanayake and Johnson75 Shiraishi et al.,85 Hierons and Johnson,86Johnson87 Jedrezejowska et al.,88 Williams* Xintaras and Burg90 Lotti and Moretto91

aModerate effects only and possible other etiological factors.

no consistent changes with time in the electrophysiologic findings in the subjects.76 In all workers, the maximum motor conduction velocity and terminal latency in the right ulnar and peroneal nerves were normal, as were the amplitude and latency to peak of the right ulnar and sural action potentials. There were no significant differences in the values obtained in the examinations before and after exposure period. No evidence of impaired neuromuscular transmission was demonstrated. Needle electromyography responses showed no abnormalities. The authors used the measure of NTE inhibition in lymphocytes as a monitor of the occupational exposure to DEF and merphos. NTE was inhibited about 40 to 60%, approaching the preexposure values 3 weeks after the end of the exposure. Since no effect on the physiology of the peripheral nervous system was observed, the authors concluded that equally high levels of inhibition of NTE activity (70 to 80%) are required in humans, as in animals, to trigger the neurotoxic response. Neurotoxic effect is independent on the inhibition of ACh.11Axonal degeneration is followed by degeneration of myelin sheath cells in the peripheral nerves, and in some cases, the degeneration of tracts within the spinal cord.72 Bidstrup et al. first reported cases of delayed neurotoxicity from an organophosphorous pesticide in 1953.77Two research chemists, working with the experimental pesticide mipaphox, experienced weakness and unsteadiness of gait two or three weeks after recovery from an episode of acute poisoning. One developed bilateral foot drop from which he recovered, while the other progressed to a flaccid paralysis of the lower extremities, and had not improved after two years. Leptophos (phosvel), which is known to cause delayed neurotoxicity, has also produced paralysis in humans and buffaloes.78 Neuropathy, caused by EPN and leptophos is related to repeated occupational exposure with inadequate precautions; apparently slight cholinergic effects were often experienced. A few cases with methamidophos and trichlorfon involved substantial occupational exposure. It caused severe acute poisoning prior to neuropathy development, but most of the cases involved accidental or deliberate ingestion of quantities that might well have been fatal but for medical intervention. In case of suicide by a mixture of pesticides including chlorpyriphos (about 20 g diluted in petroleum distillates), Osterloch et al. found that erythrocyte and peripheral nerve AChE levels were about 22% of normal and that nerve NTE was about 30% of normal.79 They predicted that treated survivors of severe poisoning by chlorpyriphos might develop delayed neuropathy. This was confirmed in another case of suicidal poisoning with chlorpyriphos (about 300 mg/kg/b. w.). Very low levels of lymphocyte NTE were found 30 d after this heavy intoxication. Typical moderate polyneuropathy developed in the following days (Lotty and Moretto, citation by EHC1).

16

Human Toxicology of Pesticides

De Jager et al. described a patient with a purely motor neuropathy, with muscular wasting and weakness of both upper and lower limbs, after ingesting an extremely high quantity of parathion (150 g), dissolved in methylalcohol.81 EMG demonstrated signs of acute denervation with normal conduction velocities in motor and sensory nerve fibers. This indicated predominantly axonal degeneration. Changes in sural nerve biopsy consisted of slight axonal degeneration, especially of the larger myelinated fibers, and some segmental demyelination. The authors are convinced that this patient had a delayed polyneuropathy. They suggest that only a massive exposure to parathion with extensive artificial respiration and charcoal perfusion, as it was in the cited case, might cause polyneuropathy; in experimental intoxications caused by ACh excessiveness, animals die from cholinergic symptoms long before neuropathy can develop. Polyneuritis and paralysis have been reported as a consequence of intoxication by malathion, parathion, merphos, and omethoate.92-96 In these cases, interference of impurities or other etiological factors is possible. According to Lotti et al. omethoate has negligible potential to cause delayed neuropathy.97 Hyporeflexia was observed in agricultural workers exposed to OP compounds. It is considered a possible sensitive test for diagnosing chronic intoxications with OP compounds.98 Preliminary results of the International Epidemiological Study on Health Effects of OP Pesticides demonstrated some changes, indicating toxic neuropathy in exposed agricultural workers.99-100 Short reviews on OP neurotoxicity were prepared by Kaloyanova, Batora, Seppalainen, Johnson.100103 E. ELECTROMYOGRAPHIC STUDIES According to Roberts and Wilson and Jager et al., subclinical neuropathy is demonstrated by EMG changes.104105 Neuropathy target esterase of human lymphocytes was proposed as a predictive monitor for delayed neuropathy effects.106 The importance of EMG for early diagnosis has been confirmed by other research, conducted by Roberts.107 Organophosphorous pesticide factory workers have been examined electromyographically, and a relation between work with OP compounds and low voltage EMG in response to supramaximum ulnar nerve stimulation has been demonstrated. Workers with low voltage EMG also average low conduction velocities in both the fastest and the lowest motor nerve fibres. A comparison of the maximum conduction velocity of motor nerve fibers in control and organophosphorous exposed workers showed that the latter group averages 10% lower velocities than the control group.107 Drenth et al. found in approximately 40% of 102 male agricultural workers abnormal but not persistent EMG patterns and no ChE inhibition.108 Six men occupationally exposed to OP pesticides were examined electromyographically over a period of 7 to 9 months. Despite the absence of clinical signs and symptoms of cholinesterase effects, the EMG voltage varied within a pattern, reflecting exposure. The EMG results were used to illustrate the way individual exposure of workers can be monitored and reduced by improving precaution measures.109 To investigate reported nervous effects on chronic exposure to organophosphorous pesticides, 25 pg/kg mevinphos daily was administered to male subjects for 28 d; results were compared to those of a control group. At the end of the exposure, a 7% decrease in slow fiber motor nerve conduction velocity and a 38% increase in Achilles tendon reflex force were found. No effect on neuromuscular transmission was observed. Red blood cell cholinesterase depression was 19%. These results confirmed similar deviations, found in pesticide workers.110Jusic et al. evaluated EMG neuromuscular synapse testing and neurological examination for early detection of organophosphorous pesticide intoxication.111 Two groups of healthy agricultural workers and one group of healthy spraymen have been exposed to various organophosphorous pesticides of different intensities. No significant difference between the exposed group and the

Organophosphorous Compounds

17

control groups was found. The electrically evoked muscle potential series in exposed workers remained as constant as those recorded at the control group. The frequency of different type of amplitude changes was the same in exposed and in control groups. Neurological records showed no significant deviations in the exposed workers. Only the subject with low cholinesterase activity demonstrated inconstancy. Further studies in this field are evidently necessary. Hussain et al. found that both EMG and AChE determinations are suitable for monitoring occupational exposure to anticholinesterase agents. In view of the potential advantages of EMG, its use for this purpose should be further developed and improved.112 F. CENTRAL NERVOUS SYSTEM OP pesticides affect some functions of the CNS. Cholinergic and noncholinergic mechanisms are involved in a variety of cases and long-term damages, including pathomorphological phenomena. Karczmar published a comprehensive review on this matter.113 Initial reports of persistent CNS manifestations included impaired memory, depression, impaired mental concentration, schizophrenic reaction, and instability lasting from 6 to 12 months. The 16 subjects had been exposed to organophosphorous insecticides for 18 months to 10 years.114 Later on, Dille and Smith described two cases with mental disturbances.115 The study concerned pilots working mostly with OP. One of them developed depressive phobia, and the other — fear and emotional instability. As a sequel, schizophrenic reactions have been demonstrated after heavy acute intoxication.116Kovarik and Sercl reported neurastenic manifestations in survivors after acute intoxication as did West.117118 Extensive studies performed by Metcalf and Holmes found no difference between exposed and control subjects in terms of such hard neurological signs as sensory or motor deficits.61 Exposed men showed more of the so called “soft” neurological signs, such as motor coordination deficiency and oculomotor imbalance. The psychological test battery consisted of the Wechsler Adult Intelligence Scale (WAIS), the Benton Visual Retention Test, and the Story Recall Task. The results indicated that the disfunctions most clearly seen in the exposed group include a disturbed memory and a difficulty in maintaining alertness and focusing attention. The exposed subjects mostly use a variety of such compensations as delay, avoidance, inappropriate giving up, and slowing down. Interviews independently check up on some of the psychological testing results and uniquely gather special information. The aim is to obtain a systematic and relatively objective view of the exposed men, their feelings about themselves and their symptoms (if any), any changes over time of which they may be aware, and their attention to industrial health practice, for example. Subjects with histories of multiple or severe exposure complain directly and give evidence of being slowed down and less energetic and having increasing memory difficulties. They also have slowness in tapping and calculation and greater irritatability than the minimum exposed group. Maizlish et al. investigated the neurobehavioral effects of short-term, low-level diazinon exposure among 99 granule applicators.119 They were tested before and after their work shift with a computer assisted neurobehavioral test battery. The post-shift median diazinon metabolite diethylthiophosphate (DETP) level for the exposed and control subjects was 24 and 3 ppm, respectively. The whole body exposure was calculated to be 2.1 and 0.03 mg, respectively, with a mean duration of diazinon application 39 d (SD = 12 d) before testing. No adverse DETPrelated changes in pre- or post-shift neurobehavioral function were found, although SymbolDigit pairing speed was slower among the applicators as a group. The prevalence of 18 symptoms, possibly related to diazinon exposure, was not elevated among applicators.

18

Human Toxicology of Pesticides

G. BEHAVIOR CHANGES Behavioral studies have been conducted to assess the psychiatric manifestations in workers with low occupational exposure to organophosphate compounds and no obvious signs of toxicity. Commercial pesticide sprayers and farmers recently exposed to organophosphate agents were compared to control subjects on personality tests, a structures interview, and cholinesterase levels. Depressive symptoms were assessed by the Beck Depression Inventory. Anxiety was measured by the Taylor Manifest Anxiety Scale. The commercial sprayers, not the exposed farmers, showed elevated levels of anxiety and lower plasma cholinesterase levels. Following are the principal behavioral changes: (1) difficulty in concentration, (2) slowed in information processing and psychomotor speed, (3) memory deficit, (4) linguistic disturbance, (5) depression, and (6) anxiety and irritability.120 On the basis of a comprehensive literature review, Maizlich concludes that persistent neuropsychiatric sequelae occur in approximately 4 to 9% of those with acute OP pesticide intoxication.121 Case reports suggest that symptoms generally resolve within 1 year after acute poisoning, although subtle functional changes were present 9 years later in at least 1 study. A limited number of cross-sectional epidemiological studies on workers with long-term employment or previous poisoning reveal subtle neurobehavioral effects, such as poorer performance on a battery of subtests involving intellectual functioning, academic skills, alertness maintenance, visual intelligence, and anxiety. However, these studies were not controlled for level of exposure, age, education, and alcohol consumption. Reports on asymptomatic workers with slight but measurable ChEA depression present contradictory results according to Maizlich. Behavioral studies not only reveal the real danger of some agricultural occupations from health point of view, they also reveal difficulties in work performed, for example plane crashes in cases of aerial application. The possible relationship between aircraft incidents and pesticides effect is discussed by Reich and Berner.122 They found, from 12 accidents with pilots, 8 cases with ChEA inhibition. Wood et al. reported an accident in which disturbances in coordination and the ability to regulate the speed of the airplane were found in pilots.123 Heat stress in hot climate conditions seems to play a very important role in aircraft accidents.124 Durham et al. investigated 53 subjects with differing degrees of exposure to OP compounds.125 Out of several vigilance tests, only 1 could establish some changes. No disturbance in the reaction time was detected; only in 2 subjects, hospitalized for OP pesticide poisoning, were disturbances in vigilance observed — but always accompanied with other symptoms. In the clinical cases of poisonings by OP pesticides, the behavioral impairments have been characterized by the following symptoms: fatigue, irritability, coordination difficulties, and slow thinking processes. Often these symptoms persist more than 1 year after the exposure.126 Kaloyanova et al. found out a slight deviation in reaction time and memory potentials in some behavioral tests on agricultural workers exposed to OPs.127 H. EEG STUDIES EEG investigations have defined characteristics of CNS disturbances in OP exposed workers.61128129 They found no increase in the incidence of hard EEG abnormalities such as spike activity or local slowing. The outstanding finding in EEG studies was a high incidence of lowto medium-voltage slow activity in the theta range, that is, 4 to 6 Hz activity occurred during light drowsiness in brief episodes of 2 to 4 s duration. Visual and auditory evoked responses have been examined to test the hypothesis that OP exposure might result in disturbances of CNS information processing capability. Sensory evoked responses provide a large amount of information and can be accomplished quickly, with a large number of people. Auditory evoked responses show more variability than the usual responses. They both have shown trends toward lower amplitudes and longer peak latencies in the exposure group.

Organophosphorous Compounds

19

Recently developed methods in computer analysis would yield specific information and permit the rapid identification of changes. They could possibly use EEG as a sensitive early index of CNS impairment.129 Increased delta activity, increased delta and theta slowing, decreased alpha activity, and increased rapid eye movement during the sleep of the exposed population are persistent and parallel to behavior changes. While it appears that OP anti-ChEs may induce long-lasting (up to one year) EEG changes, the currently available data relatively leave open the question of whether or not OP drug exposure evokes delayed psychic effects.113 The specific EEG findings, sensory evoked response disturbances, sleep disturbances, and deep midbrain effects of OP-anticholinesterase compounds are of major importance in the production of CNS changes. Whether long-term exposure to OP compounds can induce irreversible or only slowly reversible brain disfunction needs further intensive study. I. EYE AND VISION Eye and vision impairment in acute intoxication are well known. Long-term exposure to OP seems to produce visual impairment and eye abnormalities as well. Plestina and PiukovicPlestina reviewed existing publications; they summarized most of the available literature data about eye and vision impairments attributed to anticholinesterases or pesticides in general.130 They also gave a brief summary of their own investigation. Visual field stenosis (narrowing visual field), progressive myopia, astigmatism, edema and atrophia of the optic nerve, lenticular changes, cataracta, impaired balance, slower pupillary sphincter reaction, and low dark adaptability have been attributed to OP. Research revealed mild constriction of the peripheral visual fields and a somewhat lower dark adaptability in exposed workers, which might be connected with a possibly slower reaction of the pupillary sphincter. Abundant experience with powerful anticholinesterase miotics gathered by clinicians seems to add little support to the idea that anticholinesterases produce other eye impairments, except transient lenticular changes. At present the authors feel it is prudent to accept the findings that long-lasting, mostly reversible eye and vision impairment might be encountered in highly exposed subjects. Most of these changes could be explained satisfactorily through the known cholinergic mechanism, while others may be completely independent of the cholinesterase inhibition. The findings for workers heavily exposed to organophosphorous insecticides for a very long time are not consistent with the suggestion that this group of chemicals might be a cause of severe eye troubles in persons whose only exposure is environmental. Revsin suggests that all OPs penetrating the blood brain barrier will disturb visual function by selectively blocking the directional sensitivity of the visual integrative neurons in the thalamus.131 J. LONG-TERM EFFECTS There are no epidemiological data in relation to OP carcinogenicity.132 Only animal studies give some indication of potential long-term effects for man.99 Kaloyanova published a review of the experimental works on long-term effects.133 K. EFFECT OF INDIVIDUAL COMPOUNDS ON HUMANS Parathion is one of the most hazardous representatives of the OP group. It is highly toxic and often causes lethal poisonings, mainly because the symptoms of intoxication are manifested after a latent period. Even a very short exposure to parathion, if massive, can provoke severe intoxication. Such was the case reported by Thiodet et al. of a 17-year-old worker, who after 3 d work with parathion, manifested the following symptoms of poisoning: severe headache, loss of consciousness, lung edema and azotemia and glycemia.134 Carini et al. reported the parathion

20

Human Toxicology of Pesticides

poisoning of an agricultural worker with a liver injured from alcohol abuse; only a 4-h exposure to a low concentration of parathion caused a poisoning with lethal issue.135 The data of Orlando et al. show that at continuing contact, an adaptation toward parathion occurs.58 Studies with 537 agricultural workers showed that 40% of the subjects exposed to parathion had a progressive decrease in the symptoms manifested at the first contact. Most probably, this is only a seeming adaptation, since changes in the clinical laboratory investigations are observed. In subjects with moderate intoxication, a deficit in the resorption of phosphates was found on the 18th day, attributed by the authors to reversible tubular injuries. After an agricultural worker was exposed to parathion for 3 years, such symptoms as dizziness, severe headache, vomiting, diarrhea, and sweating were observed. A half-day occupational exposure, once in 15 d during the course of 4 years, resulted in anorexia, diarrhoea, many days of epigastralgia, and breathing difficulty.136 For the poisoning diagnosis and exposure evaluation, paranitrophenol in urine and ChEA was determined. The results of blood and urine analysis showed that parathion concentration in blood correlates well with paranitrophenol concentrations in urine (r = 0.56). At the same time, no correlation between the levels of parathion in serum and cholinesterase, or of cholinesterase and excretion of paranitrophenol in urine, was found.137138 Milthers et al. analyzed the symptoms of severe acute parathion intoxication in 20 patients of the Center for Control of Poisonings in Copenhagen from 1952— 1962.139 The following symptoms were found: gastrointestinal — in all patients; neurological (cramps, coma etc.) and vertigo — in 17 patients, kidney — in 15 patients, and respiratory — in 12 patients. The latent time for the symptoms to appear was from 20 min to 24 h. The death of 8 of the patients was caused by: shock — 2 patients, lung edema — 1, pneumonia — 1, lung artery embolia — 1, cramps — 2, and atelectase with pancreatic necrosis — 1 patient. Sometimes, besides the known symptoms of OP compound intoxication, some rare symptoms are observed. They are ascribed to the effects of parathion: death due to thrombosis of vena saphena interna without any intravenous injection, being applied (Frank, cit. after KaloyanovaSimeonova et Fournier), hypothermia up to 34°C combined with deep hypotonic coma, and hyperthermia with pupil dilatation.140142 Monov describes the picture of apoplexy with hypertension and anisocoria in a woman poisoned by parathion.116 Wakatsuki reported paralysis of the larynx, due to parathion intoxication.143 Ishikawa observed an atrophy of eye nerve following parathion.144 A rather dangerous formulation is methylmercaptophos(sistox). In view of the great number of intoxications it caused, it was forbidden in the U.S.S.R. Rosin analyzed 222 case histories of persons intoxicated by methylmercaptophos and established that the dermal route of penetration was the most probable compared to inhalatory or oral penetration, it had a longer latent period (3 to 8 h).145 The earliest symptoms of intoxication are giddiness with blurred vision, a headache located mainly in the parietaltemporal area, and general weakness. Later on nausea, vomiting, pains in the epigastric and abdominal area, and diarrhea appear. Pallor of the skin and membranes and furred tongue are observed, as well as moderate tachycardia and less often bradycardia, dull cardiac sounds. Single crepitations are detected in the lungs. Better expressed are the changes in the nervous system — apathy and sleepiness or on the contrary, excitement and irritativeness. Almost all sufferers show a moderate sweating, cooling extremities, and cyanosis of fingers and toes. In more severe intoxications, these symptoms are better expressed. Not infrequently, in severe forms of intoxication, loss of consciousness, weakness, vomiting (sometimes irresistible), and profuse diarrhea are noted. Cramplike twitches of the facial muscles, fingers, and toes and clonic-tonic cramps of the upper and lower extremities are characteristic. Pupil reaction is absent in the majority of the intoxicated, the tongue is furred, and the skin is pale and cyanotic. Rosin considers the absence of myosis, salivation, bronchial spasm,

Organophosphorous Compounds

21

and bronchorrea manifestation, which are leading in the symptomatology of OP compound intoxications. Of 121 workers exposed to metasistox for 1 to 18 d, gastrointestinal manifestations were found in 70, fatigue and weakness in 29, and headaches in 15; hypersecretion, tremor, and ataxia were observed in 5 subjects. The inhibited ChEA serum recovered within 30 d after treatment.146 Tilsner described metasistox poisonings with prolonged development.147The first symptoms appeared 60 h after the intoxication, and death after 81 h. Fatty degeneration of the liver was found, which could be a possible cause of the death. One case, described by Redhead, is quite characteristic of occupational poisonings in agriculture.148 It concerns a worker, in a specialized group, engaged in plant spraying over the course of 5 years; his daily exposure was from 20 min to 6 h. During the last 6 weeks of this period he worked as an adviser to aerial metasistox spraying. At the same time he was engaged with the preparation of the solution and the cleaning of the containers. He felt headaches, nausea, and dizziness 2 weeks after the beginning of this work; these complaints grew from day to day up to the weekend. They renewed with the beginning of the next work week, when new symptoms appeared, such as anorexia, loss of concentration, and lower cholinesterase activity — 7 units/ 100 cm3 vs. the standard 40 to 80 units/100 cm3. The ChEA was up to 43 units 8 d after discontinuing this work, and 13 d later the person recovered. One worker has shown acute erhythrodermia, followed by polyneuritis, two weeks after stopping a continuous metasistox spraying149 High temperature (36 to 40°C) potentiates the toxic effects of anthio upon cotton farming workers.150 An investigation on 12 agricultural workers, occupationally exposed to malathion during 6 months, revealed ChEA inhibition and SGOT, SGTP, and serum aldolase depression in 11.151 Gardner and Iverson investigated 119 subjects who had been exposed to malathion to a different degree.68 After aerial application of 95% solution against mosquitoes during an encephalitis epidemic in Texas in 1966,6 of the subjects showed signs of nausea, headache, and weakness, without ChEA inhibition. Selassie and Lester described 8 cases of malathion intoxication among workers unpacking the preparation; they became dusty when the wind blew against their faces.152The patients were transported to a hospital 130 km from the farm. Two of them died during the transportation, and the others were hospitalized 8 h after the exposure. Four acute malathion poisonings in children were reported in Israel in 1969. They had washed their hair with malathion solution. The laboratory analysis revealed hyperglycemia and glucosuria, which rapidly recovered after atropine and pralidoxine treatment.153 Stevens reported inhibition of liver microsomal metabolism due to malathion exposure.154 To assess the effects attributed to malathion that escaped from an overheated tank at a chemical plant, Markowitz et al. surveyed sailors presumably exposed on board a nearby tanker, as well as control group of sailors.155The exposed subjects more commonly reported five body systems or functions as affected, compared with the controls. The head, the eyes or vision, and bowel movements are known to be affected in OP intoxications. Verification of OP intoxication was reportedly based on substantial depression of plasma and red blood cell ChE. Baker et al. demonstrated that ChE depression in field personnel exposed to malathion was greatest in those using the pesticide brands with the highest concentrations of isomalathion and other degradation products.30 Pesticides meant for home use raises the question of hazard, not only are the people performing this operation at risk, so are the inhabitants. Vandekar reported his observations during folithion application for mosquito control in Nigeria.156He established the existence of a real danger for intoxication of children living in such houses after treatment. The development of the intoxication is favorable, leading to a rapid recovery. A relationship was noted between the clinical symptoms and ChE inhibition.

22

Human Toxicology of Pesticides

Menz et al. investigated workers who produce dichlorphos at an approximate concentration of 0.7 mg/mg3 in the air of the working environment.157 Observations were performed in the course of 1 year. No deviations were found either in the hematological and biochemical indices or in the urine analysis, except for a moderate ChE inhibition in plasma and erythrocyte cells. The significance of ChE determination is underlined not only as an indicator of exposure, but as a more sensitive index than the direct determination of DDVP in blood. Matsushima described occupational dermatitis as an effect of exposure to dichlorphos.158 Kandelaki reported 11 cases of intoxication with chlorphos (trichlorfon, dipterex) and trichlormetaphos.159 The first symptoms of intoxication were headache, dizziness, vomiting, sounds in the ears, general weakness, dull epigastric pains, sleep disturbances, liver pains, pollakiuria, lacrimation, leukocytosis, lymphopenia, and accelerated SRE. After treatment all the patients were discharged from hospital in good condition. After repeated contact with the chemicals, some of the subjects complained of joint pains, headaches, insomnia, general weakness, and stinging in the eyes. Six intoxications by the dermal route were described. At prolonged contact with chlorphos and trichlormetaphos the skin grows coarse, dry, and cracked. Folicular ceratitis, infiltrates, hyperhydrosis, and hyperemia are observed. Tsapko found functional liver changes at poisoning with chlorphos.160 Ikuta described cases of acute poisoning with trichlorphon.161A farmer ingested about 65 cm3 of 50% trichlorphon solution, and the intoxication developed with coma and myosis. Heart hypertrophy was established; no deviations were found in the liver function. The treatment included atropine and pralidoxim. After 38 d polyneuropathy was diagnosed; serum ChEA recovered on the 29th day. After an acute intoxication with trichlorphon, polyneuritis with shoulder pains, paresis and paralysis of the lower extremities, reduced tactile sensibility, absence of peritoneal and some other reflexes, diffuse muscle dystrophy, and cyanosis were observed. Babkina162and Shutov and Barankina163considered the consequences of chlorphos intoxication (dipterex), observed in 3 cases. Paresthesia with leg and arm pains appeared 10 d after severe intoxication. Polyneuritis was diagnosed 2 months later, based on paraesthesia and the presence of motor, sensory vegetative, and trophic disturbances. A slow improvement of the impairments was noted after 2 months. Holmes et al. reported 2 cases of moderate acute intoxication with meviphos (phosdrin).164 The symptomatology was similar to that of parathion or zarine intoxication. A rapid excretion of dimethylphos was established; it ended 50 h after exposure to mevinphos. In 1 of the cases, fibrinolysis was registered, and in the other, a marked tendency toward blood hypercoagulation was found, which was underlined by the curve of thrombin production. Hematuria that persisted more than 8 d was observed in 1 of the patients. In both cases the therapy had a good effect. In the case of severe mevinphos intoxication of an 18-year-old girl, Stoeckel and Meinecke reported plasma ChEA inhibition in the course of 3 months and of erythrocyte ChEA inhibition in the course of 5 months.165 Chezzo et al. reported a higher sensitivity to OP intoxications in subjects who had been exposed to OP compounds for many years.166 The authors explained this phenomenon as sensitization to acetylcholine. ChE activity in such cases was not different from that of subjects who had not been exposed before the intoxication. The sensitization to phosdrin was confirmed by Bell et al.167It concerned a worker, who had twice worked with phosdrin in a vineyard. Weiner reported a case of bronchial asthma, followed by polysensitization in the course of three weeks, after acute phosdrin intoxication.168 A short contact with household dust and different chemical substances was able to provoke an allergic reaction. Perron and Johnson presented data about a case of intoxication, with strong ChEA inhibition, after a 3-week exposure to bidrin.169 The development of the disease revealed an interesting

Organophosphorous Compounds

23

picture. A respiratory paralysis developed 6 d after hospitalization, in spite of the applied treatment with atropine and pralidoxim. The symptoms required a 22 d hospital treatment to disappear; ChEA reactivation needed several months in addition. Conyers and Goldsmith described a symptomatic psychosis in a worker who had performed desinsection of sheep with diazinon.170 Intoxication with diazinon emulsion was observed in a cattle herd and 3 herdsmen. One of these workers and 32 animals died.171 Banerjec172 described pericarditis resulting from an acute diazinon intoxication; acute OPC intoxication was also reported by Dochev and Latifyan173 and Constock et al.174 L. BIOLOGICAL MONITORING OF OP EXPOSURE Data on the relationship between exposure and ChE inhibition are shown in Tables 2 and 3. In principle, ChE activity correlates with the amount of pesticides absorbed in the organism. This is the reason ChEA is a specific test for exposure to OP compounds. ChEA inhibition is commonly found in workers exposed to organophosphorous compounds. Simpson et al. investigated agricultural workers exposed to OP compounds and OCP through processing cotton in Australia.175 The OP compounds used were methylparathion, mevinphos, and methyldemeton. The chemicals were applied by spraying. In February and March 1972 the whole blood ChEA was determined. In 50% of the subjects it was lower than the normal values, and in 4 workers it was significantly lower. At the repeated determination of ChEA in March, ChEA inhibition was found in 24 of the 30 investigated workers. Holmes published the results of a survey on Colorado farmers who had been exposed to OP pesticides for a period of 7 years (1955-1961).176 From a total of 419 investigated subjects, 70 had been hospitalized. ChEA inhibition was established in 40% of the workers. Among the personnel servicing the aerial spraying, this proportion was even higher: in 86% of the mixturers and 90% of the fillers, ChEA inhibition was observed. Kalic-Philipovich et al. found lower blood ChEA in 17.72% of the workers engaged in the production of OP compounds.177 OP metabolites in urine are also very sensitive indicators and in principle, should correlate with the exposure. As yet, the correlation of alkylphosphates with health effects has not been well studied. More studies in this aspect have been done with the parathion metabolite pnitrophenol and, recently, in connection with urinary alkylphosphates. An occupational study was conducted by Hayes et al. for a firm employing 22 pest control operators (PCOs), exposed to 3 organophosphorous insecticides.178 The exposure levels measured were less than 131.0 pg/m3for vaponite, 41.0 |ag/m3for diazinon, and 27.6 pg/m3for dursban. Hayes et al. analyzed 24-h urine samples for alkylphosphates and showed the presence of metabolites of these 3 pesticides. The effect of this exposure was reflected in a statistically significant inhibition of plasma acetylcholinesterase (AChE) among the PCOs as compared to a sex and age matched control group. There were no significant differences in the mean RBC AChE values of either group. The authors stated that only the combination of air sampling, urinary alkylphosphate ChE determination, and physical examination presents a balanced picture of the degree of exposure. The airbom concentrations of guthion 50 WP (azinphos-methyl) were measured near workers spraying with orchard air blast equipment; they were reported to be in the range of 0.02 to 0.11 mg/m3. The level of guthion on the body patches ranged from 1.8 to 18.8 ng/cm2. The cholinesterase assays revealed no depression of either RBC or serum ChEA on exposure days greater than 15% of the pre-exposure levels.179These did not exceed the variations observed in the control group. No orchardists were found to be suffering from any ailment. The pre-exposure values of urinary metabolites ranged from 42 to 137 pg/24 h, whereas the spray day 1 values ranged from 117 to 1754 jixg/24 h.

24

Human Toxicology of Pesticides TABLE 7 Clinical Symptoms of Different Grades of OP Poisoning and Corresponding ChEA Values9,190,191

Level of poisoning

Clinical symptoms

Mild 60% reduction of ChEA

Weakness, headache, dizziness, diminished vision, salivation, lacrimation, nausea, vomiting, lack of appetite, stomach-ache, restlessness, myosis, moderate bronchial spasm; convalescence in 1 d

Moderate 60-90% reduction of ChEA

Abruptly expressed general weakness, headache, visual disturbance, excess saliva tion, sweating, vomiting, diarrhea, bradycardia, hypertonia, stomach-ache, twitching of facial muscles, tremor of hand, head, and other body parts, increasing excitement, disturbed gait, and feeling of fear, myosis nystagmus, chest pain, difficult respiration, cyanosis of the mucous membrane, chest crepitation; convalescence in 1-2 weeks

Severe 90-100% reduction of ChEA

Abrupt tremor, generalized convulsions, psychic disturbances, intensive cyanosis of the mucous membrane, edema of the lung, coma; death from respiratory cardiac failure

Excretory levels of parathion metabolites — paranitrophenol correlate with exposure. The peak reached 8 h after the beginning of the exposure. The mean maximum values of pnitrophenol are reported to be 79.2 pg/h with a range of 30 to 168 pg/h. The excretion of pnitrophenol falls to a nondetectable level by the 5th to 8th day after exposure. The increase of ambient temperature stimulates the excretion. The mean amount of parathion absorbed and excreted as paranitrophenol is 2.78 mg for 4 to 8 d. This dose represents 0.02% of the lethal dose (LD50) for rats.180 As stated by Wolfe et al., the mean parathion respiratory exposure is 0.02 mg/h.180Durham et al. studied the correlation between dermal and inhalatory exposure and excretion of parathion.181 By calculating the excreted p-nitrophenol, they found that dermal exposure represented 80 to 90% of the total quantity absorbed in the body. Thus, total urinary excretion of p-nitrophenol varied from 0.67 to 7.9 mg. Respiratory exposure was responsible for 0.13 to 0. 76 mg, and dermal absorption from 0.54 to 7.15 mg p-nitrophenol. This calculation has been supported by a special volunteer study that eliminates one of the two routes of exposure, the dermal or the inhalatory in different individuals. When skin was well protected, the total p-nitrophenol excretion was 0.006 to 0.088 mg, which represented the inhalatory exposure; when the skin was not protected it was 0.597 to 0.666 mg. The estimated dermal exposure represented 0.40 to 1.95% of the exposure potential measured by dermal pads. For other OP pesticides, limited information is available about specific metabolites. A daily oral dose of 16 mg azinphos methyl for 30 d increased the excretion of anthranolic acid. Using EMG as measure of exposure is not recommended. As an early indication of neuropathy, the changes in EMG will appear in some period after exposure. Fifty-five cases of urinary schistosomiases in children were treated with metrifonate in 3 doses reaching up to 10 mg/kg/b.w. at 2-week intervals. Repetitive activity was recorded over the thenar muscles in 3 cases, following supramaximal stimulation of the median nerve in the wrist at maximum erythrocyte ChE inhibition.182 No change in evoked muscle action potential amplitude was detected. 1. Exposure Tests as an Early Indication of Health Impairments As previously mentioned, OPs act mainly by inhibiting the enzymes cholinesterase and pseudocholinesterase, which are responsible for hydrolyzing ACh at synaptic sites.183'191 The enzyme inhibition is almost irreversible. The correlation between ChEA and the clinic signs of acute poisoning is reasonable (Table 7).

Organophosphorous Compounds

25

Signs and symptoms of poisoning by organophosphorous compounds occur when more than 50% of the ChE or erythrocyte AChE is inhibited. The recovery of blood cholinesterase takes about 3 weeks in patients with mild poisoning. However, the recovery of synaptic AChE appears to be very rapid; signs and symptoms disappear within 24 h in patients with mild or moderately severe poisoning. The plasma ChE decreases, but it is normalized more quickly than that of the cell. After a severe intoxication, the reduction of enzymes lasts up to 30 d in plasma and up to 3 months in erythrocytes.80 If the rate of ChE inhibition is rapid, the correlation between the inhibition of blood ChE and the severity of symptoms tends to be good. When the rate of ChE inhibition is slow, the correlation can be low or nonexistent. This can happen during long-term occupational exposure, because the body adapts to the high levels of accumulated acetylcholine. In general, the acute cholinergic effects of severe organophosphorous poisoning correlate well with cholinesterase inhibition. Chronic moderate exposure results in cumulative inhibition of the RBC and plasma enzymes. The appearance of symptoms depends more on the rate of fall in ChEA, than on the absolute level of the activity reached. Workers may exhibit 70 to 80% inhibition of RBC and plasma cholinesterase enzymes after several weeks of moderate exposure, without manifesting cholinergic symptoms. At first exposure, individuals may develop symptoms even after inhibition of cholinesterase activity is less than 30%. This is the reason why some authors also failed to find a correlation between symptoms and ChE levels.183'188 ChE screening to predict the health effects of chronic low-level exposure is limited. Petkova, on the basis of her results in several groups of workers (n = 155) occupationally exposed to OP pesticides during application (tractor sprayers, mechanics repairing spray equipment, sprayers in public health sanitation, and greenhouse workers), stated that ChEA determination does not seem to have a leading role in the assessment of health effects of a chronic exposure.189 During this study, the depression of serum ChEA, if any, was within the range of physiological variations. A reverse correlation was established between erythrocyte ChE and paranitrophenol in urine after exposure to methylparathion. No correlation with serum ChE was established. Erythrocyte ChEA was accepted as a better biological indicator of chronic exposure. Roan et al. provide data for the aerial application of OP pesticides.188 The data suggest that erythrocyte and/or plasma ChE values are not as sensitive indices of ethyl or methyl parathion absorption as the concentrations of these compounds in the serum are. There has also been an indication that assays of serum samples via GLC are even more sensitive than urine pnitrophenol measurements. Levels of metabolite considered alone are not guides to hazard. Pesticides that have very different toxicides may yield identical acidic metabolites. Thus, the level of metabolite in urine, after it is exposed to sufficient amounts of the very toxic parathion-methyl to depress blood ChEA up to 50%, will be much less than the identical metabolites, to fenitrothion, a compound of about 40 times lower toxicity.1 Davies et al. underline that alkylphosphates in urine are very sensitive indicators for OP, but not for individual compounds.192 Urinary phenolic metabolites, when present as components of these molecules, are sensitive indicators for exposure to individual compounds. Exposure to and absorption of guthion 50 WP (azinphos-methyl) were estimated in orchardists who were involved in mixing, loading, and application.179 Air monitoring and patch techniques were used to estimate exposure; the alkyl phosphate excretion and cholinesterase inhibition were measured to estimate absorption. All workers had quantifiable levels of alkyl phosphate following exposure, and the 24-h urine samples provided a more reliable estimate than first morning voids. There was no depression of either RBC or serum cholinesterase exceeding the variations observed in the control group. A

26

Human Toxicology of Pesticides

high correlation was observed between 48-h alkyl phosphate excretion and the amount of active ingredient sprayed. In the case of parathion exposure, concentrations of dimethyl phosphate in the first urine exceeding 0.4 |LLg/ml are associated with cholinergic illness. No changes in erythrocyte or plasma ChEs at average of 10 (ig p-nitrophenol in urine were present. Hayes states that absorption of parathion is tolerated without illness and with little or no reduction of ChE activity, as long as the concentration of p-nitrophenol in urine does not rise much above 60 to 80 pg/h (2 ppm), assuming average urine excretion of 30 to 40 ml/h.193 Wolfe et al. demonstrated that /?-nitrophenol excretion levels correlated with parathion exposure. It increased rapidly after spraying, then promptly decreased.180 The average peak excretion level (about 170 pg/h) occurred 87 h after exposure began. Excretion became insignificant 5 to 8 d after exposure. Hayes et al. analyzed urine samples for the presence of alkyl phosphates in 22 pest control operators who applied vaponite, diazinon, and dursban; they used the alkyl phosphates as exposure indicators.178 The air samples collected for 8-h exposures showed levels below the recommended threshold limits. Alkylphosphates were present in 96% of the 8-h specimens of the operators. The specific metabolite values detected in the samples were (presented as group mean ± 1 SD): 176.1 ± 9 pg/8h for DMP, 48.3 ± 58.6 for DEP, 5.6 ± 3.2 for DMTP, 8.3 ± 9 for DETP. Of the urine specimens collected, 96% contained DMP and/ or DEP. Low levels of DMTP and DETP were present in 28% of the samples. Urine samples collected from 2 persons not previously exposed to OP showed levels below the detection capability of the method. For employees of the company who were not actually involved in the application, very low levels ( 5 g/kg

REFERENCES 1. Solvjanski, M., Popovic, D., Tasic, M., and Solvjanski, R., Intoxications with dinitroorthocrezol, A rc h . H ig . R a d a T o x ic o l., 22, 329, 1971. 2. Heyndrickx, A., Mayes, R., and Tybergheyn, F., Fatal intoxication by man due to dinitroorthocrezol (DNOC) and dinitrobutylphenol (DNBP), Overduck unit de Mededelingen van de Landbrokhogeschool an de Opzoekingstations van de stasi de gent. DEEL XXIX, 3, 1964. 3. Prost, G., Vial, R., and Tolot, F., Dinitroorthocresol poisoning involving the liver, A rc h . M a i. P r o f., 34,556, 1973. 4. Conso, F., Gibaud, G., Girard-Wallon, C., Alix, M., and Proteau, S. J., Intoxication professionelle par une preparation herbicide contenant de ioxynil, Arch. Hyg. Travail, 585, 1973. 5. Chateau, M. S., Parant, C., Larche-Mochel, M., and Doignon, J., Les dermatoses professionelles dues aux triazines. A propos d’un cas d’ecz&me de contact a simazine, A r c h . M a i. P r o f , 43, 8, 659, 1982. 6. Hashimoto, Y., Makita, T., Mori, T., Nishibe, I., Nogushi, T., and Watanobe, S., Preclinical experiments on the antidote against monofluoracetic acid derivatives poisoning in mammals, W h ith e r R u r a l M e d ., Proc. 4th Int. Congr. Rural Med., Usuda (Tokyo), 1969, 1970, 59. 7. Iwasaki, I., Nawa, H., Hara, A., Takagi, S., and Hyodo, K., Agricultural organofluoride poisoning, F lu o r id e , 3,3,121, 1970.

Chapter 13

COMBINED EXPOSURE I. INTRODUCTION In agriculture and public health, different pesticides are very often applied simultaneously during the same season. Therefore, a combined effect could be expected from the combined action of the pesticides. The clinical picture of such an intoxication has not yet been clarified, and some authors even reject the possibility of diagnosing it. The difficulty comes from the fact that at a long-term exposure to small quantities of pesticides, injuries may be difficult to differentiate from impairments of other etiology. The general population is also subjected to a combined pesticide exposure from environment and food. Murphy et al. analyzed the results of a 4-year study on blood and urine pesticide residues or metabolites in the general population.1About 28,000 persons, aged 6 to 74 years, from 64 communities in the U.S. were studied. Total DDT was found in 99% of the population, pentachlorphenol in 79%, dimethylphosphate in 12%, and beta-benzenehexachloride in 14%. About 25 other residues were found in lesser amounts. The toxicological significance of pesticide residues in the organism is not clear. Sometimes they are accompanied by isolated biochemical changes whose toxicological implications should be carefully evaluated; they could be indicating either an adverse effect or only an enzyme shortor long-term adaptation.2,3 False positive associations of exposure and outcomes are inevitable; a well matched control group is not easy to find. In this respect the work of Wamick and Carter represents a definite interest.4 They performed a 4 year study on workers occupationally exposed to various pesticides. They used about 50 tests to check the different organs and body systems in 70 men exposed to pesticides and 30 controls. Slight differences were found, but they were not in the same direction in the different studies. Exposure seems to increase variance in the values since nine of the tests had significantly greater standard deviations for the exposed group. The study is not conclusive concerning the existence of a chronic effect from a moderate exposure to pesticides. Kaloyanova performed a 2 year epidemiological study on 200 agricultural workers and 100 controls.5 Some differences were found between the 2 groups. Significantly, more frequent disturbances of the nervous system (neuroses), respiratory system (bronchitis and emphysema), and the gastrointestinal tract and liver, as well as of the cardiovascular system (hypoxia of myocardium and hypertension) were observed in the exposed group. Among the laboratory investigations the more frequent leukopenia, raised bilirubin, reduced serum albumin and increased alpha-globulins should be noted, as well as the activation of some phagocytosis functions. These changes do not have an essential clinical value for the single individuals, but they are characterizing the process. Under a combined pesticides action, manifestations of antagonism are posssible, which should decrease the adverse effect. It is well known that prior exposure to organochlorine compounds prevents, to some extent, the effect of organophosphorous compounds: in rats, pretreatment with aldrin increases the lethal dose of parathion sevenfold. A ChEA increase, provoked by organochlorine compounds, is a possible mechanism of this antagonism with organophosphorous compounds.6 At the same time, manifestations of potentiation may also develop, at work with several organophosphorous pesticides.

161

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Dinman reported dichlorphos and chlordane intoxication in a chemist who had worked without observing the necessary preventive measures.7 Dinman noted a greater inhibition of CNS symptoms, as well as a more rapid recovery of erythrocyte ChEA compared to that of plasma. Steigalo et al. have observed the intoxications of children in Kirgisia.8 The children consumed fruits treated with a mixture of DDT and chlorophos. Three of these intoxications developed comparatively mildly; changes in the internal organs were not established by the objective examination. The rest of the children had pronounced intoxications: gastroenteritis was observed and, on the eigth day, symptoms of myocarditis and hepatitis. Blood changes were not noted, and after 2 to 3 weeks the manifestations of intoxication faded away. A repeated examination 5 months later detected dull cardiac sounds and spleen painfulness in only a few children. Blood ChEA was significantly increased up to the end of the first month after intoxication. The authors attributed the increased ChEA to the combined effect of the two compounds. According to them, DDT compensated for the inactivating effect of organophosphorous compounds and led to ChEA increase. Severe intoxications due to combined exposure to organophosphorous and organochlorine substances have also been reported. Ingestion of 200 cm3diazinone and DDT mixture has caused tachycardia, cramps, dehydration, and hyperthermia up to death on the 10th day. The possibility of a long-term action of the diazinone metabolites and the existence of a synergism between the products of degradation of DDT and diazinone has been assumed.9 The existence of a toxic potentiation between EPN and malathion has been proved. EPN inhibits the enzyme system of malathion detoxication. These facts are valid for many other organophosphorous formulations. Single cases of intoxication with rich symptomatics at combined exposure have been reported. Soubrier et al. described 4 cases of poisoning due to the application of disinfectants and insecticides.10 The first case was a worker who had been engaged in disinfection and desinsection for 20 years; he developed the following symptoms: headaches, dizziness, insomnia, weakness, and increased excitability. The second case involved a 2-year exposure resulting in headaches in the frontal area, lumbal pains, lack of appetite, asthenia, nerve excitability, and memory disturbances mainly after DDT spraying; all the symptoms disappeared after changing the work. The third case, after a 1-year exposure, had headaches, itching in the eye area, poor sleep, and dizziness. The fourth case, after 1 to 2 years of exposure displayed dyspnea attacks of an asthmatic type, usually after spraying organophosphorous compounds or working with formaldehyde. Exposure to parathion, DDT, and phosdrin twice a week in the course of 2 years has provoked muscle weakness, abdominal pains, myosis, muscular dystonia, and increased salivation (Brachfeld and Zavon).11 Parathion and cupric sulphate, sprayed in the course of 1 d by the same agricultural worker, has provoked gastroenterological, respiratory, and neurological disturbances with partially affected consciousness (Thiodet et al.).12 Often exposure to pesticides is influenced by physical factors. Pesticides applied with tractor sprayers exposed to heat stress result in more frequent health deviations, especially in the nervous and cardiovascular systems, the intestines, liver, etc. These changes have been attributed to the complex action of the chemical and physical factors.13 Based on the available literature about the health effects of a great number of pesticides, we attempted to group these effects by organs and systems.

II. RESPIRATORY SYSTEM The effects of pesticides on the respiratory system are reported by Lings, Barthel, Lehnigk et al., etc.1416

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163

Lings studied a group of fruit growers who used a total of 92 different pesticides, with the active ingredients of 156 spray formulations.14 Each individual was in contact with 13 substances on the average (3 to 27), the most often used being captan, paraquat, parathion, azinphosmethyl, diquat, amitrol, benomyl, and simazin. The author interviewed 181 workers and performed the Wright peak flow meter test and an X-ray examination of the chest. Symptoms related with spraying were present in 40%, lung symptoms (coughing, expectoration, dyspnea, or a combination) were in 19%. The Wright test was administered to 178 persons — in 18.5% the peak flow was reduced by more than 10%. Relevant X-ray findings (accentuation of pulmonary markings, infiltration) were observed in 23.8%. The author compared the symptoms and the positive findings of the paraquat users with those of nonusers. People exposed to paraquat suffered more frequently and had lung effects, although the statistical significance was low. As an indirect control group, 132 farmers were interviewed. The questionnaire responses showed that the frequency of symptoms was not significantly higher among those who had used pesticides (biocides). A higher percentage of farmers demonstrated breathlessness, while fruit growers had more frequent coughing and expectoration, as well as headaches. The author did not perform the Wright peak flow meter test and X-ray examination on any farmer, which made the interpretation of the results difficult. Nevertheless, he concluded that exposure to biocides seemed to cause lung disease, which was characterized by the following principal features: pneumonia (more or less transient round infiltration), and chronic progressive pulmonary fibrosis. Lehnigk et al. used an adequate control group in their study.16They found respiratory function disturbances in workers exposed to pesticides. Barthel underlined the need for epidemiological investigations of pesticidal aerosol effects on respiratory systems.15

III. LIVER AND KIDNEYS The International Workshop on Epidemiological Toxicology of Pesticide Exposure concluded that the most promising tests for assessing the liver function in people exposed to pesticides are: alkaline phosphatase, aldolase, omithinecarbamoyltransferase, SGOT/SGPT ratio, and the LDH ratio.17 Stoyanov found about 53 to 59% increased SGOT and SGPT in the pilots and aeromechanics he studied.18AF changes were present in 6 to 9%. In 44% of the investigated people, an increased gamma-glutamyl-transpeptidase activity was observed. However, the lack of an adequate control group makes the interpretation of the results difficult. Petkova and Jordanova19found increased aspartate-aminotransferase and omitinaminotransferase, decreased cholinesterase, as well as depressed alkaline phosphatase and glutamyltranspeptidase in people exposed to different groups of pesticides, mainly OP, OCP, dithicarbamates, carbamates, etc. The authors consider these findings a demonstration of nonspecific, subclinical, reversible functional changes in the liver. Bezuglyi and Kaskevich reported disturbances in the liver functions of agricultural pilots.20 They found more frequent changes in serum proteins. Hypercholesterinemia and hyperbilirubinemia were found in young persons. All tests in the control group were negative. The authors considered these findings an indication of the hepatotoxic effect of pesticides. Trendafilova et al. reported changes in the lipid metabolism of greenhouse workers; betalipoproteins and total phospholipids were increased.21 The changes were more pronounced in workers with a shorter duration of service. The authors suggested that an adaptation takes place with increased duration. Zolotnikova recommended using histidase activity in the blood serum as an early indicator of hepatopathies due to pesticide exposure.22 She found increased histidase in 69% of the 40 workers investigated; cholinesterase activity in serum was inhibited in 58% of the examined workers. Increases in alanilaminotransferase, histidase, alkaline

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phosphatase, and bilirubine were found in aeromechanics. More frequent impairments of the respiratory organs, skin, and subcutaneous tissue, as well as radiculitis, were observed.23 Bezuglyi and Komarova reported functional hyperbilirubinemia (syndrome of Giebery) in workers exposed to different groups of pesticides in greenhouses, orchards, and vineyards.24 They studied 228 persons with long-term exposure. In 16 persons (7%), the syndrome was present. Bilirubin levels of 20.5 to 34.2 pmol/1 were measured. The transaminases and proteins in the serum were normal. Giebery syndrome (increased indirect bilirubin without hemolysis and slightly expressed icterus) was accompanied by asthenia, higher fatigability, sweating, dryness in the mouth, and pains in the right subcostal area; the liver increased about 1.5 to 2.5 cm. Phenobarbital, as an inductor of microsomal enzymes in hepatocytes, contributed to the reduction of bilirubin down to the norm. In subjects having long-term contact with pesticides, mainly organophosphorous and organochlorine, disturbances in some metabolic processes were found. The authors underlined the need to observe an appropriate diet to normalize the oxidation reduction processes. Tocci et al. studied several parameters of liver and kidney function, as well as amino acid levels in the blood of people exposed to large amounts of pesticides.3 The results indicated changes in 30% of the people studied, namely high levels of several amino acids in the plasma, higher SGOT, alkaline phosphatase, increased serum osmolarity, and creatinine. The phosphorus reabsorption index decreased in 16% of the workers. The authors recognized the difficulty in assessing these effects which might have been related to either cellular damage or beneficial cellular adaptation. The negative findings of medical observation of people working with pesticides are also of interest, and their publishing has been encouraged. A special investigation on kidney function in persons with long-term exposure to pesticides was performed by Morgan and Roan.26 They observed 65 subjects, agricultural workers and employees of a factory that produces pesticides, as well as 25 control subjects; 14 had manifested symptoms of intoxication in some periods prior to the investigation. They were exposed to DDT, organophosphorous compounds, and toxaphen. During the last 6 months they all were healthy. The investigation showed that their kidney function was not disturbed. Gombert et al. did not find differences in the glomerular filtration or the index of phosphate resorption in exposed subjects or control subjects.27

IV. IMMUNOTOXICITY Pesticides may exert a deleterious effect on lymphoid organs, and in this way disturb the immune response of delayed and nondelayed types. They may reduce the nonspecific resistance of the organism to infections, spontaneous mutations, and malignant cells. Some pesticides are haptens, capable of binding to proteins to form complex antigens. This leads to allergy development, which can be demonstrated as contact dermatitis, rhinitis, bronchitis, bronchial asthma, pharyngitis, and allergic diseases of other organs and systems.28 A. ALLERGY TO PESTICIDES Allergic diseases in agricultural workers are often related to pesticides.2930 Vasher and Vallet published a study on the frequency and etiology of allergies supposedly caused by pesticides and fertilizers used in France for 10 years.31 Out of a total of 9864 allergies, 690 (14%) could be attributed to pesticides and fertilizers. According to the clinical picture, the authors arranged them in the following order:

Combined Exposure •

• • • • •

165

Allergies with predominating skin manifestations, 511 cases including 412 cases of contact dermatitis and 89 cases of atopic and other dermatitis (urticaria and angioneurotic edema of Quincke, simple erythema nodosum, pigment erythema, nonthrombopenic purpura, and erythrodermia) Respiratory allergy, 117 cases (including asthma in 17% of the cases) Blood manifestations, 15 cases, e.g. isolated eosinophilia, hemolytic anemia, leukopenia, agranulocytosis, and thrombopenic purpura Serum disease, 8 cases Anaphylactic shock (as an exception), 4 cases Otorhinolaryngologic disturbances, 28 cases (rhinitis, sinuitis, laryngitis, otitis)

Cardiovascular, neurological, gastrointestinal and endocrine disturbances attributed to allergies without any toxic manifestations have been found after long-term exposure to pesticides, and they are cautiously discussed by the authors. By means of the “removal-repeated accepting” test the authors established: manifested occupational allergies in 11 cases; symptoms of undoubted occupational origin, but without any possibility to identify the allergen, in 15% of the cases; poly sensibilization of predominantly occupational character (low significance of nonoccupational allergens) in 40%; poly sensibilization with predominant nonoccupational character in 16%; and exclusively nonoccupational sensibilization (complications due to to occupational stimulation) in 16% of the investigated. The authors presented a detailed table of the allergies provoked by different pesticides and fertilizers. Dermatitis due to sensibilization from multiple contacts with organochlorine, organosulphurous, organophosphorous, organomercurial, and other pesticides was described by Kambo et al.32 Kozintseva et al.33 studied the possible formation of circulating antipesticide antibodies as evidence of heteroimmune response to the effect of tetramethyl thiuramdisulphide, DDT, chlorophos, and ziram. The data showed that serum antibodies were generated in 20 of the 24 subjects. The authors found that the intensive generation of antibodies induced by these pesticides correlated with the results of other tests evidencing the immunological phase of the allergic process. Using serological reactions as an additional test to confirm the allergic character of the diseases with chemical etiology was proposed. Popov et al. found latent allergy in 31.68% of the women working in greenhouses.34The most common allergen was acrex (11.8%). A polyvalent allergy to different pesticides was also established. Karimov studied skin sensitivity of 233 cotton growers to different pesticides.35 In 27 (4.2%) of 633 samples, he found positive reactions to OP pesticides. B. IMMUNOSUPPRESSION Katsenovich et al. studied the immune status of patients with different degrees of combined insecticide intoxication.36 Modem methods were used to assess the T- and B-system of immunity. The quantitative deficit in T-lymphocytes was accompanied by a reduction of their functional activity. The number of B-lymphocytes was increased in most patients. The ratio of T- to B-lymphocytes was altered to varying degrees, depending on the grade of intoxication. Some suggestions were made for developing an autoimmune processes. Polchenko and Zinchenko studied 12-year-old children living in rural areas of limited or intensive pesticide application. A significant decrease of the titers of isochemaglutinins and immunoglobulins G, A in serum, and particularly of immunoglobulin A in saliva, was found.

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Differences in T-lymphocytes were also found. The authors explained the increase in most of the respiratory diseases of the exposed children as disturbances in the immune defense mechanisms. Zolotnikova reported disturbances in the immunological reactivity of persons working with pesticides in greenhouses.38 An increased quantity of skin microflora was found, as well as a decrease in the phagocytic activity of leukocytes. Changes in the humoral factors of immunity were less expressed, e.g., the titration index of antibodies and hemolytic activity of serum. Allergic skin diseases are more frequent in people who worked from 1 to 5 years, while bronchial asthma, liver and kidney damage, and vegetative impairments are more frequent in workers with over 5 years service. Bezuglyi reported, from clinical and epidemiological studies, more frequent nonspecific diseases of the cardiovascular, nervous, and hepatobiliary systems, gastrointestinal tract, female sexual organs, and the eyes (conjunctivitis and blepharitis) in persons subjected to long-term exposure to pesticides.39 Surveys on the general population of agricultural regions or on people using household pesticides show higher general morbidity. They also show an increase in diseases of the respiratory ways (asthma, sinuitis, and bronchitis), leukemia, conjunctivitis, and blepharitis (Chezzo et al.).40,41 C. HEM ATOLOGICAL CHANGES A 4-year longitudinal epidemiological study was performed by Romash and Dorofeev42 on agricultural workers exposed to OCP, OP, phenol nitroderivatives, copper organic compounds, etc., in order to determine the effect of pesticides on peripheral blood. Workers from a food production plant were investigated as a control group. The most demonstrative indicators were considered to be a decreased hemoglobin content, an erythrocyte count showing morphological deviations, neutropenia, lymphocytosis, eosinophilia, granulation, and vacuolization in the cytoplasm. Cytochemical reactions showed increased fetal hemoglobin in 21 % of the cases and increased the quantity of ciderocytes. Decreased myeloperoxidase activity, increased alkaline phosphatase activity in neutrophiles and succidehydrogenase and lactatodehydrogenase in lymphocytes were found. Similar results were reported by Sutneeva.43 She found decreased hemoglobin, erythropenia, leukopenia with neutropenia, and eosinophylia. Tsvetkova et al.44 studied cation proteins (low molecular basic proteins related to the enzyme function) in the granulocyte lysosomes of agricultural workers exposed to pesticides. A significant reduction of cation proteins was established compared to the control group, which was better manifested during the active pesticide application period. These findings are believed to indicate disturbances in cellular metabolism, decreased synthesis processes. Long et al. studied the amount of pesticides used and the blood and urine values.45 The total pesticide applied by the high use group and the erythrocyte sedimentation rate showed a negative correlation in the respective subjects. Positive correlation was established between the total pesticide applied and the blood uric acid, as well as bilirubin 1-min values. The authors discuss these results with caution and suggest further studies. D. NERVOUS SYSTEM Pesticides may provoke functional or morphological disturbances in the central, peripheral, and vegetative nervous systems. Usually, nervous system effects are connected with specific compounds (organomercurials, organophosphates, etc.) which produce specific effects. Only single publications related to combined exposure.

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TABLE 1 Visual Disturbances in Workers Exposed to Pesticides Frequency of disturbances

Type of disturbances Decrease of corneal sensitivity Impaired color discrimination (chrom) Narrowing of visual field (achrom) Enlargement of the blind spot Reduced adaptation

Exposed workers

Control group

23.0

5.8

20.3 58.2 64.4

8.7 14.4 14.2

16.6

14.2

Fokina studied winegrowers and gardeners exposed to copper-containing OP, carbamates, OCP, etc.46,47 She found an increased frequency of nervous system diseases, manifested in vegetative vascular dystonia, asthenic vegetative syndrome, hypothalamic syndrome, and diseases of the peripheral nervous system. These persons also showed more frequent cerebral vascular diseases (cerebral atherosclerosis and hypertension). Rheoencephalographic estimations demonstrated decreased blood input in different brain areas of exposed persons. An adequate control group was used to compare the findings. The statistically significant changes were only discussed. Roder and Lindner studied agricultural workers exposed to OCP, OP, dithiocarbamates, aromatic nitrocompounds, etc.48 In 15 of 51 persons, subjective symptoms indicating neuropathy were present. Decreased nerve conduction velocity was demonstrated on the peroneal nerve. E. VISION In the last few years increasing attention has been paid to eye impairments and visual abnormalities caused by pesticide exposure. Since the eye is a highly sensitive organ that reacts rapidly to irritating stimuli, especially occupational ones, Kalic-Filipovic supports some ophthalmological indices for early diagnosis of occupational intoxications.49 An improved preventive control is proposed, including a more systematic investigation of the combined effect of pesticides, in which ophthalmological investigation should take its place. The author found that 38.8% of the subjects employed in the pesticide production he investigated lost colordiscriminating ability (compared to 8% in the control group); in 25% of the cases, the subjects suffered lower dark adaptation. Nuritdinova performed ophthalmological studies on 638 workers, aged 20 to 50 years, who had from 1 to 8 years occupational exposure to phosphorous and organochlorine compounds.50 In 80% of the subjects, symptoms of chronic intoxication have been established (sympathicotonia, asthenia, polyneuritis, and encephalopathy). Eye changes were found in 11% of the cases. Allergic conjunctivitis was found in 33 cases, blepharitis in 6, retinal angiopathy in 28, and retrobulbar neuritis in 2. Glazko investigated 260 agricultural workers chronically exposed to pesticides and complaining of eye disturbances (Table l).51 Clinical investigation revealed symptoms of chronic intoxication. Neuroophthalmological manifestations were more frequent among those who had had symptoms of chronic intoxication by pesticides with systematic effect.

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Fournier described neurobulbar neuritis, provoked by inhalatory exposure to organochlorine and organophosphorus compounds.2Campbell described neurobulbar neuritis after exposure to pentachlorphenol, dichlorobenzol, and DDT (used to control insects in wooden furniture).52 Imazumi observed conjunctivitis, hypervascularization, and corneal ulcerations as a local effect of pesticides.53 According to Sugaya, eye injuries due to pesticides in Japan are as frequent as those due to trachoma.54 In 1966 California, 25% of the occupational diseases due to pesticide exposure involved the eyes. Trusiewiczowa reviewed the effects of pesticides on the visual system.55 She summarized the most frequent changes following long-term exposure: myopia, retinal degeneration, optic nerve damage, accomodation spasm, and glaucoma. She underlined the necessity of more studies in this field.

V. LONG-TERM EFFECTS The data on teratogenicity, mutagenicity, and carcinogenicity of pesticides in animals are numerous; human data are rather scarce. Data on individual chemicals are given under the respective chapters. Here, only a few publications dealing with long-term effects of combined exposure should be mentioned. Joder et al. studied lymphocyte cultures from 42 pesticide applicators and 16 control.56They found a marked increase in the frequency of chromatid lesions. This phenomenon was especially pronounced among workers exposed to herbicides. A few chromatid exchange figures were found in the exposed persons. Of special interest are the data on a presumably combined long-term effect described by Bartel.57The retrospective cohort study examined cancer morbidity in a group of men with more than 5 years occupational exposure to pesticides, beginning their work between 1948 and 1978. The ranging order corresponded to the distribution expected in the general male population, except for bronchial carcinoma, where 50 cases were observed against 27.5 expected. The doseeffect relationship was suggested by the positive correlation between the duration of employment and the lung cancer mortality. The smoking habits of the exposed men were not different from those of the general population. Roan et al. compared some reproduction indices in 314 families of agricultural pilots and 170 control families.58 They found no differences in the number of male and female children, spontaneous abortions, or birth defects. The authors recommended similar studies on female subjects exposed to pesticides. They recognized that the comparatively limited sizes of their study groups, was not a sufficient basis to accept a complete absence of pesticide effect on the reproductive parameters studied.

VI. CONCLUSION After a multiple combined exposure to pesticides workers may be manifested by a more or less specific pathology and allergy. Most often, combined occupational intoxications are subacute and observed mainly when agricultural workers do not follow the prescribed hygiene. Chronic forms are less frequent and found in workers who produce and formulate pesticides. Chronic intoxication from combined pesticides in agriculture requires profound study. The review of literature on chronic occupational intoxications showed a number of diagnostic difficulties, even in cases of the isolated action of a single pesticide. Only a few cases of chronic

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TABLE 2 Summarized Symptoms and Syndromes at Combined Exposure to Pesticides Nervous system Vision Respiratory system Cardiovascular system Liver Kidneys Gastrointestinal tract Hemopoietic system and blood Skin

Asthenovegetative syndrome, vegetative polyneuritis, radiculitis and diencephalitis,vegetative vascular dystonia, brain sclerosis Retrobulbar neuritis with reduced visual acuity, angiopathy of the retina, reduced corneal sensitivity, narrowed visual field Chronic tracheitis, initial pneumofibrosis, lung emphysema, bronchial asthma Chronic toxic myocarditis, chronic coronary insufficiency, hypertonia, hypotonia Chronic hepatitis, cholecystitis, hepatocholecystitis, disturbance of detoxifying function and other liver functions Disturbances, expressed in: albuminuria, azotemia, urea, creatinin, reduced excretory function, low clearance Chronic gastritis, duodenitis, ulcus, chronic colitis (hemorrhagic, spastic, quasipolyposic neoplasms), secretory disturbances, (hypersecretion, hypoacidity up to achylia), motor disturbances Leukopenia, increase of reticulocytes and lymphocytes, eosinopenia, lymphopenia, monocytosis, anemia Dermatitis and eczema

TABLE 3 Scheme for Medical Examinations Prophylactic examinations Obligatory (in out patient clinic) Serum ChE, serum protein fractions, SGPT, SGOT, routine blood and urine tests

Recommended (in out patient clinic) Total protein, total bilirubin alkaline phosphatase, aldolase ECG, Ro-graphy of the lung

In case of intoxication In cases of suspected poisoning, in the presence of some clinical symptoms, the tests are carried out in a hospital Serum ChE, serum protein fractions, SGPT, SGOT, routine blood and urine test, total protein, total bilirubin, alkaline phosphatase, aldolase, ECG, Ro-graphy of the lung, lactate dehydrogenase, (LDH1/LDH5 ratio, omithyl carbamyltransferase, leucinaminopeptidase, blood lipids (beta-lipoproteins, total cholesterin), specific metabolites, EEG

intoxications of agricultural workers are reported in literature. The problem with the combined effect of pesticides is even more complicated. Chronic intoxication is not the only possibility for the adverse effects pesticides have on man. Alterations in the structure of the general morbidity may also be an expression of the combined chronic effect of pesticides. The difficulties in diagnosing “chronic combined intoxication with pesticides” are evident; however, such intoxication is quite realistic. Therefore research efforts should be developed in this direction. Table 2 attempts to summarize the data already cited, as well as some from additional sources.57 71 Such a synopsis reveals that damage of all organs and systems in the organism is possible under combined pesticide exposure.

170

Human Toxicology of Pesticides

REFERENCES 1. Murphy, R. S., Kutz, F. W., and Strassman, S. C., Selected pesticides residues or metabolites in blood and urine specimen from a general population survey, E n v iro n . H e a lth P e r s p e c tiv e s , 48, 81, 1983. 2. Fournier, E., Phenomenes biochimiques observees en niveau du foie au cours des hepatites toxique, in C o m p ts r e n d u s T6 r e u n io n n a tio n a l d e s c e n tr e s d e lu tte c o n tr e le s p o is o n s , Paris, Nasson, 1966, 12. 3. Tocci, P. M., Mann, J. B., Davies, J. E., and Edmunson, W. F., Biochemical differences found in persons chronically exposed to high levels of pesticides, In d . M e d . S u rg ., 38, 188, 1969. 4. Warnick, S. L. and Carter, J. E., Some findings in a study of workers occupationally exposed to pesticides, A rc h . E n v iro n . H e a lth , 25, 265, 1972. 5. Kaloyanova-Simeonova, F., P e s tic id e s T o x ic A c tio n a n d P r o p h y la x is , Bulgarian Academy of Science, Sofia, 1977, (in Bulgarian). 6. Spassovski, M., Experimental investigations on combined effect of some organophosphorous and organochlorine insecticides, PhD Thesis, 1962, (in Bulgarian). 7. Dinman, B., Acute combined toxicity of DDVP and chlordane, A rc h . E n v iro n . H e a lth , 9, 765, 1964. 8. Steigalo, E., Givogliadov, L., and Druchevskaja, Z., On the combined effect of organophosphorous and organochlorine compounds on the growing organism, G ig . P r im e n . T o k s ik o l. P e s tits . K lin . O tr a v le n ii, 498, 1968, (in Russian). 9. Monseur, J., Intoxications par melange d’insecticides chlores et phosphores, B u ll. M e d . L e g . T o x ic o l. M e d ., 7, 6,450, 1964. 10. Soubrier, R., Bresson, R., and Tolot, F., Manifestations pathologiques en relation avec l’emploi de pesticides en disinfection et de disinsectization, A rc h . M a i. P r o f., 26, 6, 339, 1965. 11. Brachfeld, J. and Zavon, J., Organophosphate (Phosdrin) intoxication, E n v iro n . H e a lth , 6, 11, 259, 1965. 12. Thiodet, J., Massonnet, J., Milhaud, M., Colona, P., and Tenati, E., Intoxication par insecticides a base de parathion. Intiret des methodes de rianimation respiratoire dans le traitement des formes graves, Sti Midicales des Hopitaux d’Alger A. M. Fivrier, 1960, 183. 13. Izmirova, N., Petkova, V., and Beraha, R., Sanitary-hygienic investigations on mechanized application of pesticides, H ig . Z d r a v e o p ., 24, 6, 537, 1981, (in Bulgarian). 14. Lings, S., Pesticide lung: a pilot investigation of fruit-growers and farmers during the spraying season, B r. J . In d. M e d ., 39, 4, 370, 1982. 15. Barthel, E., Irritating and allergic effect of aerosol pesticides on respiratory ways and the problems of expertise, Z. G e s a m te H y g . Ih re G r e n z g e b ., 19, 11, 678, 1983, (in German). 16. Lehnigk, B., Thiele, Ed., and Wosnitzka, H., Disturbances of respiratory functions due to the effect of agricultural chemicals, Z. E rk r. A tm u n g s o r g a n e , 164, 3, 267, 1985, (in German). 17. Anon., Report of an International Workshop on Epidemiological Toxicology of Pesticides Exposure, A rc h . E n v iro n . H e a lth , 25, 339, 1972. 18. Stoyanov, T. G., Changes in some biochemical indices at chronic effect of pesticides, T ra n sp . M e d . V esti, 24, 1,26, 1979, (in Bulgarian), (summary in German and Russian). 19. Petkova, V. and Jordanova, Ju., Enzyme changes at chronic exposure to pesticides, P r o h l. H ig ., 5,133,1980, (in Bulgarian). 20. Bezuglyi, V. P. and Kaskevish, L. M., Some indices of the functional state of liver in flight personnel engaged in aerial chemical operations, G ig . Tr. P r o f. Z a b o l., 13, 10, 52, (in Russian). 21. Trendafilova, R., Charakchiev, D., Krasteva, S. and Kolarska, S., Laboratory data in subjects with occupational combined exposure to pesticides, S a v r e m . M e d ., 34, 1, 21, 1983, (in Bulgarian). 22. Zolotnikova, G. P., On the early detection of functional liver disturbances in women with occupational exposure to pesticides in greenhouse conditions, G ig . S a n it., 2, 24, 1980 (in Russian). 23. Izmailova, T. D. and Derevyanko, L. D., Hygienic characteristics of working conditions and the functional state of technics from agricultural aviation, G ig . T r. P r o f. Z a b o l., 9, 27, 1986, (in Russian). 24. Bezuglyi, V. and Komarova, L. M., On the syndrome of Gilbert in subjects exposed to pesticides, V ra ch . D e lo . 3, 105, 1984, (in Russian). 25. Kaskevich, L. M. and Djogan, L. K., The state of some metabolic processes in subjects exposed to pesticides, G ig . Tr. P r o f. Z a b o l., 10, 47, 1983, (in Russian). 26. Morgan, D. and Roan, C., Renal function in persons occupationally exposed to pesticides, A rc h . E n v iro n . H e a lth , 19,5,633, 1969. 27. Gombert, A., Beat, V., Bonderman, P., and Long, K., Seasonal pesticide exposure relationships including renal phosphate reabsorption and urinary alpha-aminoacid nitro loss, A rc h . E n v iro n . H e a lth , 21,2, 128, 1970. 28. Zaykov, C., Immunotoxicology of pesticides, in Toxicology of Pesticides, Proc. of a Seminar, Sofia, Bulgaria, 1981, World Health Organization Regional Office for Europe, Copenhagen, 78, 1982. 29. Gervais, P., Les accidents allergiques en agriculture, L a R e v u e P r a tic ie n , 25, 3841, 1965. 30. Gervais, P., Reactions allergiques aux substances chimique de composition definie, Physiopathologie, Clinique, Diagnostique, Masson et Cie, 1968, 350.

Combined Exposure

171

31. Vacher, J. and Vallet, G., Les allergie supposees aux pesticides et engrais. Dix annees d’observations partielles en France, A r c h . M a i P r o f., 29, 6, 336, 1968. 32. Kambo, Y., Matsushima, S., Matsumura, T., Kuroumo, K., and Suzuki, N., Studies on patch tests in contact dermatitis caused by pesticides, W h ith e r R u r a l M e d ic in e , Proc. 4th Int. Congr. Rural Med., Usuda, 1969, (Tokyo), 1970, 55. 33. Kozintseva, P., Kuznetsova, L., and Zinchenko, D., Clinical significance of the detection of antipesticide circulating antibodies, G ig . P r im e n . T okik. P e s tits . K lin . O tr a v le n ii, 345, 1973, (in Russian). 34. Popov, I., Darlenski, B., and Miadenova, S., Latent allergy to pesticides in the developing of occupational contact dermatites in greenhouse workers, D e r m a to l. V e n e r o l., 23, 2, 21, 1984, (in Bulgarian). 35. Karimov, A. M., Occupational skin diseases in cotton growers caused by chemical poisons and measures for their prevention, G ig . T r. P r o f. Z a b o l., 14, 35, 1970, (in Russian). 36. Katsenovich, L. A., Rusybakiev, R. M., and Fedorina, L. A., T- and B-systems if immunity in patients with pesticide intoxication, G ig . T r. P r o f. Z a b o l., 4, 17, 1981, (in Russian). 37. Pol’chenko, V. I. and Zinchenko, D. V., Immunity indices in epidemiological studies of children from districts with intensive and limited use of pesticides, in M e th o d o lo g y , O r g a n iz a tio n a n d S o m e M a s s I m m u n o lo g ic a l E x a m in a tio n s, S u m m a r ie s o f th e R e p o r ts o f a n A ll-U n io n C o n fe r e n c e , A n g a r s k 1 9 8 7 , Petrov, R. V., (Ed.), Moskva, Angarsk, 1987. 38. Zolotnikova, G. P., Disturbances of the immunological reactivity of organism under exposure to pesticides in greenhouse conditions, G ig . T r. P r o f. Z a b o l., 3, 38, 1980, (in Russian). 39. Bezuglyi, V. P., The effect of pesticides and their complexes on the development of non-specific diseases, 7, 102, 1980, (in Russian). 40. Chezzo, F., Berretti, P., Perini, G., Belloni, G., and Vigan, L., Long-term effects of pesticides on human health, epidemiological research on the morbidity of rural population, M in e r v a M e d ., 59, 2949, 1968. 41. Janicki, K., Leukemias in the Krakow region in the years 1961-1968 and contamination of the environment by pesticides, A c ta M e d . P o l., 13, 1,49, 1972. 42. Romash, A. V. and Dorofeev, V. M., Significance of some indices of peripheral blood in the diagnosis of chronic intoxications by pesticides, L a b . D e lo , 11,679, 1984, (in Russian). 43. Sutneeva, G. I., Sanitary-hygienic conditions of application and toxicological properties of the mixture of keltan, chlorofos and copper hydroxide, G ig . S a n it., 8, 101, 1973 (in Russian). 44. Tsvetkova, T., Atanassova, K., and Andonov, S., Cation proteins content of granulocytes in agricultural workers, H ig . Z d r a v e o p ., 27, 3, 216, 1984, (in Bulgarian). 45. Long, K. L., Beat, V. B., Gombart, A. K., Sheeta, R. F., Hamilton, H. E., Falaballa, F., Bonderman, D. P., and Choi, U. Y., The epidemiology of pesticides in a rural area, A m . In d . H y g . A s s o c . J ., 30, 298, 1969. 46. Fokina, K., Rheoencephalographic diagnosis of vascular pathology of the brain in persons exposed to a complex of pesticides, G ig . T r. P r o f. Z a b o l., 4, 49, 1980, (in Russian). 47. Fokina, K. V., Nervous system disturbances in persons working with cuprious and other pesticides, V ra c h . D e lo ., 9, 113, 1984, (in Russian). 48. Roder, H. and Lindher, M., Electroneurographic studies of agricultural workers exposed to pesticides, E r g e b . E x p . M e d ., 41, 379, 1982, (in German). 49. Kalic-Filipovic, D., Dodic, S., Savic, S., Prodanovic, M., Arsenijevic, M., Guconic, M., and Kidakovic, A., Occupational health hazards in the production and application of pesticides, A rc h . H y g . R a d a , 24,3,333,1973. 50. Nuritdinova, F., The effect of pesticides applied in agriculture upon the organ of vision, M e d . Z d r a v o o h r . U z b ., 6, (in Russian). 51. Glazko, I., The frequency of eye impairments and visual functions in persons working with toxic chemicals in agriculture of Donets region, G ig . Tr. P r o f Z a b o l., 14, 1, 34, 1970 (in Russian). 52. Campbell, A., Neurological complications associated with insecticides and fungicides, B rit. M e d . J ., 2,415, 1952. 53. Imazumi, K., Atzumi, K., Horie, E., Mita, K., Takano, Y., Goto, I., Nakumura, R., and Kashii, K., Ophthalmic disturbances due to agricultural chemicals in Japan. W h ith e r R u r a l M e d ic in e , in Proc. 4th Int. Congr. Rural Med., Usuda, 1968 (Tokyo), 1970, 47. 54. Sugaya, R., Studies on pesticide poisoning among farmers, in W h ith e r R u r a l M e d ic in e , in Proc. 4th Int. Congr. Rural Med., Usuda, 1968 (Tokyo), 1970, 47. 55. Trusiewiczowa, D., Pesticides and organ of vision, K lin . O c zn a ., 85, 6, 263, 1983. 56. Joder, J., Watson, M., and Benson, W., Lymphocyte chromosome analysis of agricultural workers during extensive occupational exposure to pesticides, M u ta t. R e s ., 21, 335, 1973. 57. Barthel, E., Increased risk of lung cancer in pesticide-exposed male agricultural workers, J . T o x ic o l. E n v iro n . H e a lth ,8, 1027, 1981. 58. Roan, C. C., Matanoski, G. E., Mcllnay, C. Q., Olds, K. L., Pylant, F., Trout, J. B., Wheeler, P., and Morgan, D. P., Spontaneous abortions, stillbirths and birth defects in families of agricultural pilots, A rc h . E n v iro n . H e a lth , 39, 1, 56, 1984.

172

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59. Engberg, I., De Bruin, A., and Zielhuis, R., Health of workers exposed to a cocktail of pesticides, Int. A rc h . A r b e its m e d ., 32, 171, 1974. 60. Alexeeva, G. and Jakubova, R., The effect of pesticides on the health of population under conditions of their application in Uzbekistan, G ig . P r im e n . T o k s ik o l. P e s tits . K lin . O tr a v le n ii., 455, 1969, (in Russian). 61. Bezuglyi, V., Muhtarova, N., Buslenko, A., Kachalaj, D., Komarova, L., and Bereznyakov, I., The health state of persons with long-term occupational exposure to pesticides, G ig . P r im e n . T o k sik o l. P e s tits . K lin . O tr a v le n ii, 417, 1967, (in Russian). 62. Bezuglyi, V., Muhtarova, N., Kaskevich, L., Kachlaj, D., Komarova, L., and Bereznyakov, I., On the health state of persons from the flight-technical personnel engaged with aviation chemical work, G ig . P r im e n . T o k sik o l. P e s tits . K lin . O tr a v le n ii, 466, 1968, (in Russian). 63. Barseva, L., On the chronic effect of plant-protection chemicals and the functional state of liver in people working with them, H ig . Z d r a v ., 9, 5,491, 1966, (in Bulgarian). 64. Kagan, Y., Trachtenberg, I., Rodionov, G., Lukaneva, A., Voronina, L., and Verich, G., The effect of pesticides upon the rise and development of some pathological processes, G ig . S a n it., 3,23,1974, (in Russian). 65. Krivoglaz, B., Clinic and treatment of poisonings due to toxic chemicals, L ., 1965, 165, (in Russian). 66. Sharp, D. S., Eskenazi, B., Harrison, R., Calas, P., and Smith, A. H., Delayed health hazards of pesticide exposure, A n n . R e v . P u b lic H e a lth , 7, 441, 1986. 67. Kundiev, Y., I., Krasnyuk, E. M4, Eds., Occupational diseases in workers engaged in agriculture, Kiev, Zdorovje, 1983 (in Russian). 68. Hayes, W., Pesticides and human toxicity, A n n . N .Y . A c a d . S c i., 160, 40, 1969. 69. Kachalaj, D., Functional state of the gastrointestinal tract of warehousemen in stores for toxic chemicals, G ig . P r im e n . T o k sik o l. P e s tits . K lin . O tr a v le n ii, (Kiev), 1968, 253, (in Russian). 70. WHO Technical Reports Series, No 571, Early detection of health impairment in occupational exposure to health hazards, World Health Organization, Geneva, 1975. 71. Medved, L. I., Kundiev, Y. I., Hygiene of labour in agriculture, M . M e d ., 1981, (in Russian).

Chapter 14

EPIDEMIOLOGY OF THE ACUTE PESTICIDE INTOXICATION The available information on the epidemiology of acute pesticide poisonings is very fragmentary. Getting a clear idea of the seriousness of the problem, in the world as a whole is not possible; in some regions information is missing, because the intoxications are not registered, or not even known. Nevertheless, the WHO working group and some other authors attempt to estimate the possible number of intoxications. Based on statistical data for 19 countries the WHO working group estimated that, worldwide, there have been as many as 500,000 cases annually of pesticide intoxications. The mortality rate has been 1% in countries where medical treatment is readily available, so deaths are estimated to be about 5,000 a year.1 However, it is reckoned that the real number of poisonings is considerably greater — about 2 million per annum. About 40,000 persons die and admittedly 75% of the lethal cases occur in developing countries. That means that every 17 min a person dies of pesticide poisoning, and every 10 min 28 subjects are poisoned by pesticides.2 The WHO working group recently estimated pesticide intoxications based on the population at risk and the rate of intoxication.3 Suicide attempts were estimated to be about 2 million, occupational intoxications — 700,000, and other unintentional cases — 300,000. Mass poisoning outbreaks from contaminated food were estimated to be about 1,650. Some data on acute intoxications in different countries are given in Table 1. In past years (1956-1967), many mass poisonings were due mainly to the contamination of food products, together with the use of highly toxic pesticides, such as endrin, parathion, and hexachlorbenzene.11 The mortality rate in some of these incidents was more than 10%. After 1970 they still occurred, but for different reasons (Table 2). The real morbidity and mortality rate of pesticide intoxications is difficult to calculate in view of the poor registration and the size of the exposed population. In the publications available, the annual incidence rate varies from 6 to 79 per 100,000 agricultural (risk) population. Levine reviewed the available data on unintentional pesticide poisonings.19 The majority were likely due to occupational exposure in agriculture. The annual rates of unintentional pesticide poisonings range from 0.3 to 18 cases per 100,000 in 17 countries. Mortality rate in the U.S. has been given as 1 per 1 million; the ratio between fatal and nonfatal poisonings was 1:13 in one study and 1:75 in another, depending on the severity (Hayes, 1964, cited by Mrak20). Pesticide intoxications represent 6 to 12.8% of the total number of intoxications by solids and liquids. Parathion was the leading cause of death (49%) in the groups under 5 years of age (McCarthy, 1967, cited by Mrak20). In California the number of persons at risk is approximately 250,000. Annually 827 to 1013 cases of occupational injury from pesticides were reported between the years 1960 and 1963 (West and Milby, 1965, cited by Mrak20). Caldwall and Sundifer reported that the cases of pesticide poisonings in South Carolina were 20 per 100,000.21 Hayes and Vaughan studied mortality from pesticides in U.S. for 1973 and 1974.22 Most of the poisonings were nonoccupational and involved gross carelessness. Before 1961 the number of deaths was more than 100 per year, while in 1973 it was 32 and in 1974 it was 35. Morgan et al. studied morbidity and mortality in workers occupationally exposed to pesticides.23 Proportionate mortality patterns were similar in exposed and control groups. Skin diseases and skin cancer were exceptionally common among pest control operators. Elevated serum DDT and DDE levels appeared to characterize persons who reported hypertension, atherosclerosis, and possibly diabetes in subsequent years. 173

236 (160 occupational) 3000 unspecified 4000 30 fatal occupational 296 9 fatal (3 occupational)

1985-86

1971-76

1979

Costa Rica

Egypt

1985

1971-76

786 15 fatal 803 occupational 11 fatal (fosdrin - 5, other OP - 2)

1981

Guatemala

Hungary

787 1 fatal

3 years

France Occupational

1952-71

England and Wales

1559 occupational

1954-77

Bulgaria

Number

Period

Country

OP-3 8 9 O C -9 Carbamate - 20 Nicotine - 7 Herbicide - 221 Fungicides - 94 Rodenticides - 4 Fumigants - 9 Others - 50

OP-4 7 Nitrophenols - 36 Arsenicals - 24 Mercury compounds - 22 Methylbromide - 15 Others - 27 OP-49.5 Carbamates -15.50 Organochlorines -1 2 Gramoxone - 3.5

Leptophos, tamaron and gusathion Lanate

Above 50% OP

Kind of pesticide Acute intoxications

Type of injury

TABLE 1 Acute Pesticide Poisonings

Handling concentrates and containers Disposal of empty containers Inadequately labeled containers

Work in treated areas

Reasons for poisonings

Adamis and Szenzenstein9

Taylor et al.5

Dubrisay and Fags8

Hearn7

Sallam an El Chawaby6

Taylor et al.5

Kaloyanova4

Authors

Human Toxicology o f Pesticides

1984

1975-80

1974

Sri Lanka

California

Annually

1978

12 years

1970-77

Nicaragua

Mexico

Malaysia

Japan

395 5 fatal Annually 13,000 hospitalized 1000 fatal 1257 occupational

1376 Clinical cases (including nonoccupational) 728 men 648 women 87 fatal 204 occupational (apple orchards) 167 clinical cases 87 men 78 women 113 occupational 15 fatal 14 suicides 11 paraquat 1200 estimated 9 fatal 847 occupational 4 fatal Methylparathion - 16.5% Sevin - 11% Azodrin - 8.9% Lannate - 6.6% Gusathion Methyl - 2.3% Other OP - 14.8% O C - 1.6%

O P-6 3 Herbicides - 20 Sulphur - 19 Carbamate - 4 Antibiotics - 5 Others - 48

OP - 30% O C -6% Carbamates - 5% Herbicides - 12.5% Organosulphurus - 10% Organomercurial - 1% Antibiotics - 3% Nicotine- 6 6 Acute intoxication - 99 Skin impairment - 54 Ocular impairment - 3

Acute intoxication - 46% Eye injuries - 0.9% Nasolaryngophary ing injuries - 42.6% Others - 5.6%

73.1% suicides 17.1 occupational

Insufficient protection - 40% Poor general health - 19% Improper weather conditions - 5%

Insufficient protection - 40% Poor general health - 19% Improper weather conditions - 5%

Durham15

Jeyaratnam et al.13

Taylor et al.5

Nagera and Sanchez de la Fuente14

Jearatnam et al.I3

Sugaya and Wakatsuki"

Matsumitsu et al.12

Sugaya and Wakatsuki10

in

-4

Epidemiology of the Acute Pesticide Intoxication

176

Human Toxicology of Pesticides TABLE 2 Mass Poisonings After 1970

Country

Number

Iraq Pakistan U.S.

6000 (500 fatal) 2800 (5 fatal) 1350 (8 fatal)

Pesticide Methylmercury in food, bread, etc. Malathion (occupational exposure) Aldicarb (water, melon contamination)

Authors Bakir et al.16 Bakir et al.17 Green et al.18

On the basis of 27 pesticide intoxications in 436 citrus growers, Griffith and Duncan estimated 376 citrus fieldworker related poisonings per year in Florida.24The incidence rate was 113 poisonings per 10,000 fieldworkers; 75 were hospitalized. That is an incidence rate of 23 hospitalized cases per year for every 10,000 field workers. The estimated incidence rate for possible poisonings in citrus field workers was 295 per 10,000. A later estimate came up with 34 confirmed and 160 possible poisonings per 10,000 field workers.25 In a Philippine rice growing area the mortality rate, related to diagnosed pesticide poisoning in men aged 15 to 54, increased from 2.39 to 8.29 per 100,000 for the periods 1961 to 1971 and 1972 to 1984, respectively. The mortality rate of leukemia also increased, while the overall cancer rates have not increased significantly.26 The author discussed a possible link between exposure and the development of leukemia. Jeyaratnam et al. surveyed acute pesticide poisonings among agricultural workers in Indonesia, Malaysia, Sri Lanka, and Thailand.27 Pesticide users among agricultural workers ranged from 29.8% in Indonesia to 91.9% in Malaysia. About 10 to 20% of the pesticide users suffered an episode of pesticide poisoning during their working life. Among hospital admissions in 1983 (28 to 107 cases), unintentional occupational and nonoccupational poisoning was responsible for 32% in Malaysia, 62% in Sri Lanka, 22.7% in Thailand, and 2% in Indonesia. The percentage of suicides varied from 36.2 in Sri Lanka to 67.9 in Malaysia. The annual incidence rate of pesticide poisoning in Sri Lanka for the period 1975 to 1980 was 79 per 100,000. The equivalent rate for suicide attempts was 58 per 100,000, and for occupational intoxication it was 13 per 100,000.7 The fatality rate was about 9%.727 Acute pesticide intoxications are a high priority in developing countries. We cannot agree that these intoxications are “third world diseases” as stated by Agarwal (cited by Sim28), because this problem exists in all countries, although at a different level. Thus, in Sri Lanka two and a half times as many people were hospitalized as in the U.S., and nearly five times as many died, despite of the fact that the U.S. uses about a third part of the whole pesticide in the world. Three pesticide poisoning admissions into Jakarta hospitals take place each day, as well as in one large hospital in Bangkok. In Sri Lanka, 50% more pesticide related deaths occured in 1977 than deaths from malaria, tetanus, diptheria, whooping cough, and polio taken together.28 Epidemiological study of chronic and long-term effects is a difficult task. Many confounding factors make it almost impossible to establish a clear cause-effect relationship. Usually, the pesticides contribute to a quicker emergence of some disease already existing in a latent stage, or exacerbate some illness. The prevalence of some diseases in the mortality of two groups of different pesticide exposure may indicate such an effect. The rate of very mild subclinical intoxications would be much higher. Some indication for this suggestion comes from the biological monitoring of ChEA, performed regularly in some countries. In selected groups of farmers using pesticides, those with inhibited ChEA reach up to 30% in some countries. About 24% of 821 pesticide users in Malaysia had ChE inhibition by more than 25 to 30%.29 In Sri Lanka, 15% of the workers in a pesticide formulating factory and 25 to 30% of the workers in agriculture have manifested unsatisfactory ChEA levels. In Brazil, ChEA inhibition has been found in about 20% of the exposed workers.30

Epidemiology of the Acute Pesticide Intoxication

111

In Bulgaria, biological monitoring of ChEA is performed on all persons engaged in pesticide spraying in organized teams. The data are given in Table 3.31 In a study of self-reported pesticide poisonings and hospital admissions for poisoning, about 7% of the agricultural workers using pesticides in Malaysia and Sri Lanka had been poisoned in the course of 1 year.27 Organophosphorous compounds were responsible for the majority of acute intoxications and lethal cases. Polchenko analyzed 34,000 intoxications in 66 countries from 1945 to 1966 and came to the following principal conclusions: there was no correlation between the number of intoxications and the amount of pesticides used; 75.4% of the intoxications were produced by organophosphorous pesticides (80% by parathion); 66.6% of the intoxications were occupational; 23% of them occurred during pesticide production and 77% during application (about 20% of the latter were reentry intoxications).32 An analysis of poisoning cases in Bulgaria from 1965 to 1968 showed that 28% were of persons engaged in treated areas; for the period of 1968 to 1973 this percentage increased to 56%, due to the increased aircraft application.11 Of the total number of intoxications, 69.5% were provoked by organophosphates. Kahn reckons that officially reported cases are only a small fraction of the actual number of such poisonings.33In Dade County, Florida, 72 pesticide fatalities (46%) between 1959 and 1965 were due to parathion.20 In a study of 129 poisonings in South Texas, 98% were caused by parathion and methylparathion. In the U.S., parathion was also the leading cause of death (49%) for children under 5.20 Paraquat is often responsible for intoxications — mostly suicidal — in Malaysia, as well. From 1977 to 1981 post mortem analysis of poisoning cases showed the most commonly consumed poisons: herbicides — 326 cases (310 cases or 95% with paraquat), OP — 155 cases (85% malathion and 4% dichlorovos), and OCP — 88 cases (31.8% DDT, 26% thiodan, 18% dieldrin, and 15% BHC). Of the 565 total deaths, 54.5% were due to paraquat. In one state of Malaysia the prevalence of paraquat poisonings per 100,000 population was calculated to be 4.6% (73.4 suicides: 13.8% accidental and 1.7% occupational).28 In Sri Lanka and Malaysia, the major class of identified chemicals causing pesticide poisoning are organophosphates, 65% and 53.6%, respectively. In Thailand, bipyridiliums are responsible for 25% of the intoxications, and in Indonesia, copper compounds are responsible for 23.4%.27 The reasons for poisonings are generally the same in all countries: inadequate technical equipment, insufficient technological training, poor personal hygiene and health education, nonuse of educational protective devices, inadequate labeling and disposal of containers, use of highly toxic substances, increased working days, and work in treated areas. The “pesticide residue related illness” or “reentry poisonings” are more frequently reported. Polchenko reviewed the world literature on acute pesticide intoxications.34 Polchenko analyzed 70,000 cases of intoxication and proposed a 9 criteria classification. With some modifications, this classification is shown in Table 4. Polchenko only analyzed the nonoccupational unintentional intoxications, published in the literature.35,36 About 47% of these intoxications are in the 0 to 5 age group. The poisonings involve the use and storage of pesticides at home (12.3%), the consumption of contaminated food, or contact with pesticide residues in the environment (87.7%).

CONCLUSION Information about the epidemiology of acute pesticide intoxications is inadequate. Nevertheless, it is obvious that the problem is serious, particularly in countries without well developed and implemented preventive strategies for pesticides use.

Total

21,294 26,761 92,982 31,376 27,522 28,941 18,011

Year

1975 1976 1977 1978 1979 1980 1981 1,947 2,894 1,345 2,626 1,911 3,360 1,964

Inhibited

Before working season

9.14 10.80 5.80 6.33 6.90 11.60 10.90

% 8,033 6,484 9,345 8,618 10,079 10,758 8,458

Total 589 322 405 556 388 166 992

Inhibited

During spray season

TABLE 3 ChEA in Monitored Workers

7.33 4.90 3.30 6.45 3.84 1.45 11.70

%

1,176 1,769 2,019 2,494 2,227 2,237 2,869

Total

269 145 153 267 127 147 140

Inhibited

% 22.87 8.19 7.47 10.70 5.70 6.57 4.87

End of the working season

Human Toxicology o f Pesticides

Epidemiology of the Acute Pesticide Intoxication

179

TABLE 4 Classification of Intoxicaitons by Pesticides34 Criteria Character

Route of entry Number of intoxicated persons Grade of intoxication

Classes Accidental Occupational Industry Agriculture (including reentry) Public health Forestry Trade and other Nonoccupational Home Environment Primary Secondary (via environmental media) Intentional Suicide Homocide (criminal intoxications) Oral Respiratory Dermal Single - up to 5 persons Group poisoning - 5 to 100 persons Mass poisoning - more than 100 persons Severe Lethal Nonlethal Medium Light

The WHO/UNEP Working Group held in Tbilisi in 1987, estimated that 3 million pesticide intoxications occur annually all over the world. Suicide should be responsible for 2 million cases and occupational exposure for 700,000; the remaining 300,000 are due to other unintentional reasons. Organophosphorous pesticides, paraquat, and carbamates most often are responsible for intoxications. The mortality rate of pesticide poisonings varies from 1 to 83 cases per million relative to the development of the country and its economic structure. The incidence rate may reach 79 per 100, 000 .

Reentry intoxication is a problem recognized in some countries. It was estimated that the incidence rate of such intoxications may be about 160 cases per 10,000 workers. This kind of intoxication is mainly related to the use of organophosphorous compounds, but also to carbamates and pesticides from other groups.

REFERENCES 1. Safe use of pesticides, WHO Expert Committee on Insecticides, 20th Report, TRS No. 513, World Health Organization, Geneva, 1973. 2. Ecoforum, Ind. Toxic. Res. Centre, Lucknow, In d. T o x ic o l. B u ll., 6, 4, 19, 1982. 3. Public health impact of pesticides used in agriculture, Report of WHO/UNEP working group, May, 1988, World Health Organization, Geneva. 4. Kaloyanova-Simeonova, F., P e s tic id e s . T o x ic A c tio n a n d P r o p h y la x is , Publishing House of the Bulgarian Academy of Science, Sofia, 1977. 5. Taylor, R., Tame, K., and Goldstein, G., Paraquat poisoning in Pacific Island countries 1975-85, South Pacif. Comm. Noumea New Caledonia, Dec. 1985, T. Paper 18.

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6. Sallam, M., EI-Ghawaby, S. H., Safety in the use of pesticides, /. E n v iro n . S c i. H e a lth , B ., 15, 6, 677, 1980. 7. Hearn, C. E. D., A review of agricultural pesticide incidents in man in England and Wales, 1952, 1971, fir. J. In d . M e d ., 30, 3, 253, 1973. 8. Dubrisay, J. and Fages, J., Occupational pathology in agricultural activities. Attempts of a statistical approach. II. Occupational diseases., A rc h . M a i. P r o f., 39, 7, 459, 1978. 9. Adamis, Z. and Szenzenstein, M., Occupational poisonings in agriculture, in Konferenz iiber Sicherheitstechnik der landwissen-schaftlichen Chemisierung. Vortrage, OMKDK Technoinform, Budapest, 1978, 9. 10. Sugaya, H. and Wakatsuki, S., Countrywide investigation of clinical cases of pesticide intoxication (collected during 1970-1977), J p n . J. R u r a l M e d . (N ip p o n N o se n I g a k k a i Z a s s h i), 27, 3, 436, 1978. 11. Sugaya, H. and Wakatsuki, S., Results of a nationwide survey on clinical intoxication cases due to agricultural chemicals, J p n . J. R u r a l M e d ., 28, 3, 452, 1979. 12. Masumitsu, T., Nagata, J., Kobayashi, H., and Ono, S., Studies on intoxication due to a natural insecticide, nicotine, (Report I) N ip p o n N o s e n Ig a k k a i Z a s s h i, 29, 1,61, 1980. 13. Jeyaratnam, J., de Alwis, R. S., and Copplestone, J. P., Survey of pesticide poisoning in Sri Lanka, B u ll, o f W H O , 60 (4), 1982. 14. Nagera, R. R. and Sanchez de la Fuente, E., Pesticide intoxications in “Comarca Lagunera” during 1974, S a lu d P u h lic a M e x ., 17,5,687, 1975. 15. Durham, W. P., Pesticides and human health, in P e s tic id e s . C o n te m p o r a r y R o le in A g r ic u ltu r e , H e a lth a n d th e E n v iro n m e n t, Sheets, T. J. and Pimentel, D., Eds., Humana Press, Clifton, NJ, 1979, 83. 16. Bakir, F., Damluji, L. S., Amin-Zaki, L., Murtadha, M., Khalidi, A., A1 Roni, N., Tikritis, Dhahir, H., Clarkson, T., Smith, J., and Doherty, R., Methylmercury poisonings in Iraq, S c ie n c e , 184, 230, 1973. 17. Baker, E. L., Zack, M., Miles, J. W., Alderman, L., Dobbin, R. D., Miller, S., Teeters, W. R., and Warren, M., Epidemic malathion poisoning in Pakistan malaria workers, L a n c e t, 1, 8054, 31, 1978. 18. Green, M. A., Neumann, M. A., Wehr, H. M., Foster, L. R., Williams, L. P., Polder, J. A., Morgan, C. L., Wagner, S. L., Wanks, L. A., and Witts, J. M., An outbreak of watermelon bom pesticide toxicity, A m .J . P u h l. H e a lth , 77, 1431, 1987. 19. Levine, R. S., Assessment of mortality and morbidity due to unintentional pesticide poisonings, WHO/VBC, 86, 929, World Health Organization, Geneva, 1986. 20. Mrak, E. M., Report of the Secretary, Commission on Pesticides and their Relationship to Environmental Health, U.S. Department of Health, Education and Welfare, 1969. 21. Caldwell, S. T. and Sandifer, S. H., South Carolina pesticide poisonings, 1978,/. S. C . M e d . A s s o c ., 75, 12, 615,1979. 22. Hayes, W. J. and Vaughan, W. K., Mortality from pesticides in the United States in 1973 and 1974, T o x ico l. A p p l. P h a r m a c o l., 42, 235, 1977. 23. Morgan, D. P., Lin, L. J., and Saikaly, H. H., Morbidity and mortality in workers occupationally exposed to pesticides, A rc h . E n v iro n . C o n ta m . T o x ic o l., 9, 3, 349, 1980. 24. Griffith, J. and Duncan, R. C., Grower reported pesticide poisonings among Florida citrus fieldworkers, J. E n v iro n . S c i. H e a lth , 20, 1, 61, 1985. 25. Griffith, J., Duncan, R. C., and Konefal, J., Pesticide poisonings reported by Florida citrus fieldworkers, /. E n v iro n . S c i. H e a lth , 20, 6, 701, 1985. 26. Loevinsohn, M. E., Insecticide use and increased morbidity in rural central Luzon, Phillipines, Epidemiology, L a n c e t, June 13, 1359, 1987. 27. Jeyaratnam, J., Lun, K., and Phoon, W. O., Survey on acute pesticide poisoning among agricultural workers in four Asian countries, B u ll, o f W H O , 65, 4, 521, 1987. 28. Sim, F. G., The pesticide poisoning report. A survey of some Asian countries, International Organization of Consumer Unions, Regional Office for Asia and the Pacific, P.O. Box 1045, Penang, Malaysia, 1985. 29. Jeyaratnam, J., Lun, K. C., and Phoon, W. O., Blood cholinesterase levels in agricultural workers in four Asian countries, T o x ic o lo g y L e tte r s , 33, 193, 1986. 30. Trape, A. Z., Garcia, E. G., Borges, L. A., De Almeida Prado, M. T., Kavero, M., and Almeida, W. F., Trojeto de vigilancia epidemiologia om ecotoxicologia de pesticidas. Abordagem Preliminar Revista Bras, de Sal. Occup.,47, 12, 1984. 31. Kaloyanova, F. P., Occupational hazards of pesticides and their epidemiology, Proc. Int. Conf. Environ. Haz., Agrochem., Alexandria, Egypt, Nov. 8-12, 1983, 1,312. 32. Polchenko, V. I., Pesticide poisonings according to data from world literature, G ig . P r im e n . T o k sik o l. P e s tits . K lin . O tr a v le n ii, 1968. (In Russian). 33. Kahn, E., Epidemiology of field reentry poisoning, /. E n v iro n . P a th o l. T o x ic o l., 4, 5, 323, 1980. 34. Polchenko, V. I., Classification of pesticides, V ra c h . D e lo , 2, 151, 1972, (in Russian). 35. Polchenko, V. I., Household pesticide poisonings abroad, G ig . P r im e n . T o k s ik o l. P e s tits . K lin . O tr a v le n ii, 462, 1962, (In Russian). 36. Polchenko, V. I., Household cases of pesticide poisoning, G ig . S a n it., 10, 90, 1969. (In Russian).

Chapter 15

REENTRY PERIODS I. DEFINITION OF PROBLEM Workers may suffer significant exposure when they enter previously treated areas for further cultivation and hand-harvesting.1'3 The degree of exposure depends on many factors, including the physical properties of the pesticide and its biodegradability, the crop, the nature of the application, and the climatic conditions. In Bulgaria reentry poisonings occur in groups working on tobacco plantations up to 15 d after spraying or in persons who pick flowers sprayed with organophosphate compounds. It has turned out that the 5 d as reentry time, determined for all pesticides, did not guarantee safety.14 Data given by U.S. authors point out that this problem exists, especially in California and Florida. Spears et al. described poisonings from pesticide residues while picking fruits treated with parathion, paraoxon, etion, phosalone, azinphosmethyl, diocation, dioxan, and monooxan.5 McClure reported an incident of poisoning during grape picking.6From a total of 120 persons, 108 received symptoms after 2 weeks work in vineyards sprayed with phosdimethoate, methomyl, and zolon. The pollution of the leaves reached 57 ppm with zolon and 2.3 ppm with zolonoxon. Peoples and Maddy reported a group poisoning in California involving 118 of 120 grape pickers.7The workers had been allowed to enter the field before the required 30 d waiting period for dialifor and phosphalone. Excessive skin exposure to the chemical resulted in intoxication. Plasma ChEA was inhibited by more than 60%, and 85 of the patients were admitted to a hospital. In studies performed during the picking of pears sprayed with zolon, erythrocyte ChEA decreased insignificantly at exposure level 4 mg/h; therefore, this exposure was estimated to be an insignificant risk.8 The basic exposure in reentry intoxications occurs via skin. The formation of more toxic metabolites or interaction with other substances in the environment may take place. The pesticide residues may be more hazardous a few days after application than at the time of application. Kundiev et al. reported poisonings in sugar beet plantations after polychlorpinen treatment.9 After spraying polychlorpinen or lindane after spraying polychlorpinen of lindane highly toxic compounds, namely phosgen, hydrogen cyanide, chlorocyanide and chlorocyanic compounds, were eliminated up to the 75th day when, besides polychlorpinen, ammonium nitrate was used in the soil for fertilizing. Klissenko et al. suggested that in this case the highly toxic volatile compounds had access to the air because latches of ammonia liquor with admixtures of iron carbonyl were used.10 Iron carbonyl possibly caused the acute poisoning in humans working in the sugar beet fields. Besides ammonia and carbon oxide, other compounds were possibly formed. Later, it was proved that some other organochlorines, in the presence of nitrate fertilizers, also eliminate poisonous gases. Upon welding residual organochlorine pesticides (hexachloran and sodium trichloracetate) and fertilizers in sugar beet plantation soil emit toxic gases (hydrogen chloride and phosgen). These emissions start a week later and last 18 to 20 d after pesticide application. With annual treatment the emissions start a week later and last for about 2 months. Maximum HC1 emissions occur at higher atmospheric temperatures (during noon hours); that of phosgen occurs during the hours of maximum UV irradiation.11

181

182

Human Toxicology of Pesticides

Interactions between pesticides and fertilizers resulting in toxic gas emissions have to be further investigated. The hazard of methyl bromide fumigation for soil disinfection has been described by Van den Oever et al.12Workers cultivating soil 9 d after application may be exposed to 15 ppm.; 11 d after application no methyl bromide is detected in the air.

II. METHODOLOGY FOR ESTABLISHMENT OF REENTRY INTERVALS Methodologies for the determination of safe reentry intervals have been developed in Bulgaria, the U.S., and the U.S.S.R.1328 A unified field model for reentry intervals in the U.S. has been proposed.1920 The report of the working group on occupational exposure to pesticides details this problem in the U.S. This document discusses the problem of recognizing reentry-related pesticide illnesses, as well as the methodology for defining reentry intervals and necessary legislation.29 Nigg underlines the need for a systematic approach to the problem as well.30 He gives preference to simple but accurate investigation methods. Many variables should be taken into consideration in determining and evaluating reentry periods.3132 Nigg and Stampes consider four principal factors: (1) dusty work environment (in Florida clay it is defined as particles of 2 pm but in California about 29 to 57% particulates are from 2 to 50 pm and they settle better on foliage); (2) toxicity of pesticide; (3) transformation to more toxic compounds (e.g., oxon); (4) environmental conditions (more oxon metabolites are found in dry climate conditions).21 The authors compared the findings in California and Florida and explained the great difference in recommended reentry intervals. Kahn worked out directives to perform field studies aimed at determining safe reentry intervals for organophosphorous compounds.25 The pesticide quantity on foliage is measured in pg/cm3. It has been accepted that 20% ChEA inhibition in the plasma and 15% in erythrocytes, for 2 preliminary investigations indicated some effect. That is why such subjects were not admitted to the study. In the process of investigation, single subjects with more than 40% ChEA inhibition in plasma and more than 30% in erythrocytes, as compared with the initial levels, were removed; inhibitions of 20% and 15%, respectively, were considered reliable. Spear et al. found a correlation between foliage paraoxon content and ChEA inhibition.33 Some U.S. authors swing toward reentry determination without investigating humans. They use the relationship between pesticides on foliage and dermal LD50 for rats.3435 The OP disappearance rate is a prime consideration for determining safe reentry times. Nigg and Stamper simultaneously studied the disappearance rate of four organophosphates on fruits and leaves.36 They found that fruit and leaf surface residues were quite similar and suggested only one be analyzed for residues— preferably leaves. The disappearance rates of the four tested compounds are arranged in a decreasing order: malathion, oxydemeton methyl, dialifor, and dioxathion. The authors suggested that physical properties such as the diffusion coefficient and/ or vapor pressure, which are temperature-dependent, may account for the observed differences in disappearance rates. Nigg et al. studied the disappearance rates of acephate, methamidophos, and malathion for citrus foliage.37 Malathion had a half-life of 5.2 d, acephate — 6.8 d (mist blowers) and 12.6 d (hand gun), and methamidophos — 9.5 d (mist blowers) and 13.6 d (hand gun). Contact with citrus foliage 7 or more days after application was not deemed dangerous. It was stressed that only dislodgable residue data but not organic solvent extraction data should be used to estimate worker exposure. With special, simple equipment, small disks are taken from the foliage and analyzed.2135 37

Reentry Periods

183

The relationship between leaf residues and dermal contamination was studied. Popendorf et al. calculated that 98 to 99% of the accepted dose in exposed persons is from dermal exposure, especially through the hands.8 There was a correlation between calculated dose and the leaf residues of the pesticide. Nigg et al. found a strong positive correlation between leaf pesticide residue and pesticide flux (jig/cm2/h) onto various exposure pads, except shoulder, upper arm, and forearm pads.24The correlation coefficient for upper total exposure vs. leaf residue was 0.70; hand exposure vs. leaf residue was 0.97, and lower body exposure vs. leaf residue was 0.98. Only 1.6% of the estimated quantity of pesticide reaching the pad was excreted in urine. Zweig et al. considered the relationship between the dermal exposure (dose) and the presence of pesticide on the leaves.38 The dermal exposure was measured in mg/h. These authors found a positive correlation between these two parameters of exposure and pesticides of different groups: captan, vinclosolin, methiocarb, and carbaryl applied to different cultures. The relationship between dermal exposure and residual quantity on the leaf was expressed by the surface/ time relationship. The ratio dermal exposure: dislodgable foliar residues was within the same order of magnitude for different pesticides and crops. Skin exposure on the hands is estimated from cotton gloves, and on other parts of the body from the lint layer on the clothes. The pesticide content of the leaf is determined from 3 cm diameter disks cut out from the leaf. Dermal exposure in mg/h is calculated by multiplying the amount of dislodgable foliar residues of leaf surface in mg/cm2 by an empirically found ratio of approximately 5 x 103. Calculating reentry intervals according to EPA guidelines goes through several steps. The noneffect level in qg/kg/d is determined by calculating dermal dose — ChE response curve on rats.34 The allowable exposure level (AEL) is calculated from the NOELs for the pesticide using appropriate safety factor. It is assumed that 100% of the dose is absorbed during the 8-h working day of a 70-kg individual. NOEL includes the results of dislodgable residues, the whole body dermal dose, and a dislodgable residues dissipation curve, obtained under field conditions. Nigg and Stamper published an overview of field methods for assessing worker exposure.23 Specific attention was given to dermal absorption pads and the statistical variability of their contamination, personal air samplers, and urine analysis. It was underlined that relevant human biochemistry and physiology data, as well as urinary excretion kinetics, could be a very worthwhile prior investment. Mathematical equations for calculating reentry intervals are proposed in the U.S.S.R.28

III. STUDIES ON INDIVIDUAL PESTICIDES Zweig et al. studied the dermal exposure of strawberry harvesters to benomyl and captan.39 The ratio of the dermal amount of both pesticides was found to be similar to the ratio for the dislodgable foliar residues of the same two pesticides. The average dermal exposure was found to be 39 mg/h/person for captan and 5.39 mg/h/person for benomyl. Productivity as measured by the quantity of fruits picked, and the dermal exposure of the individuals to benomyl correlated positively; no correlation was found for captan. Similar results have been obtained for carbaryl.39 Zweig et al. studied the dermal exposure of strawberry harvesters to carbaryl.40 They estimated the carbaryl exposure from cotton gauze, light cotton gloves, and plants. The foliar residues were 7.74 (ig/cm2 1 d after application and 0.15 qg/cm2 17 d after application. The dermal hand exposure, at 3 mg/h on the first day, was the largest; on the third day it was 1.47 mg/h. With zolon in doses from 10 to 14 mg/h, no erythrocyte ChE A inhibition was provoked in pear harvesters. Variations in the decay and oxidation of parathion orange foliar residues were related to ambient weather and foliar dust. Peak levels of parathion generally occur within 2 to 3 d.41,42The

184

Human Toxicology of Pesticides

ozone concentration in the air also contributes to the conversion of parathion to paraoxon.43 Compared to its production at low dust levels, more paraoxon was produced by a factor of 4 at high dust levels without ozone and by nearly a factor 30 at high dust levels in the presence of 300 ppb of ozone. Reentry hazards and safe reentry periods in captan treated fields were also studied in the last few years.3843'45 Captan and its major metabolite, tetrahydrophthalimide (THPI), were determined as dislodgable residues on foliage and fruits, as well as in air samples and patches attached to clothing and gloves. As a biological index, the urine of workers was examined for the presence of tetrahydrophthalimide. THPI was found in the urine of field workers not protected by aspirators, but in spite of the high dermal exposure it was absent in the urine of those equipped with respirators. Respiratory exposure is believed to be the primary route. A study of workers in captan treated grape fields reached the same conclusion.45 A study by Batista et al. of a Florida citrus plantation found the half-life for carbaphenthion dissipation from leaves was about 4 d; the dissipation from soil was about 7 d.46 In the urine of 4 male workers harvesting onions in an ethyl- and methylparathion-treated field, traces or levels above the detection limit of diethyl phosphate and diethylthiophosphate were found 7 weeks after treatment.3

IV. REENTRY INTERVALS FOR SOME PESTICIDES The state of California established occupational reentry safety standards for citrus fruit, peaches, grapes, and apple. The EPA has since developed standards, but these are less stringent than the California standards.29 The norms existing in U.S. are very different. For 12 pesticides the EPA has determined a maximum interval of 48 h or the drying up of the sprayed pesticide if corresponding reentry periods do not exist. California has established reentry intervals from 1 to 45 d for 20 pesticides. For example, the EPA standard for azinphosmethyl is 14 to 24 h and California standard is 14 to 30 d. Similar to our observations, they also give different terms depending on the concentration of the applied pesticide, e.g., parathion has from 30 to 60 d on citrus cultures.29 This fact as well as the possibility of some pesticides transforming into more toxic metabolites in the environment (e.g. parathion into paraoxon) requires investigation to determine reentry intervals.3047 The largest reentry period proposed is 70 d for chlorthiophos in California citrus trees.3448 Carbamates also represent reentry hazards. Studies on reentry intervals for carbamates have been published.39’4849 Iwata et al. determined a safe dislodgable foliar level for carbosulfan and carbofuran — 0.3 |ig/m3 of leaf surfaces.48 They conducted dose-ChE response studies on rats, and proposed a 7 d reentry interval for California citrus. Using the same methodology, Nigg et al. proposed safe reentry intervals for Florida citrus groves treated with carbosulfan — 3 d for 4 lb of active ingredient/acre and 1 to 2 d for 1 lb of active ingredient/acre.49 For some pesticides, under specific conditions, no reentry intervals appeared necessary. Such is the case with difocol and deltamethrin applied to lemon trees and French beans, respectively.4750 The reentry periods accepted in Bulgaria are shown in Table 1.

V. THE PROBLEM OF PRACTICAL USE OF REENTRY INTERVALS U.S. reentry intervals are reglemented by local and federal agencies.54'56 Culver criticized the concept of worker reentry intervals as unrealistic in the long run and not

Reentry Periods

185

TABLE 1 Reentry Intervals in Bulgaria (in Days)51'53 Pesticide

Field

Dichlorphos Fosdrin Methylparathion Tamaron Vidate Dimethoate Intrathion Sayfos Actelik Pirimor Unden

— —

10 8 —

7a-5 b 15a-13b 13a—1l b —

5a —

Glass houses 6 3 — —

4 3 — —

1 5 3

a Application by tractor. b Aerial application.

a permanent solution.57 As an alternative, he suggested preventive medical programs, which should include a variety of laboratory tests to ensure no negative health effect in the working environment. The supervising physician should remove workers from the field until the source of the problem is identified and corrected; they should remain off the field until their health has recovered. It is obvious that this methodology does not ensure real prevention in certain cases involving very toxic substances and early reentering. The authors do not discuss the alternative of avoiding highly toxic substances when there is a necessity to enter the field several days after treatment. Reentry intervals are difficult to implement because of the inherent complexity of modem pest control technology, i.e., multiple chemicals, formulations, and dosage rates, as well as unpredictable climate conditions that affect the degradation of residues. However, extensive research, to identify safe reentry intervals for a large number of pesticides applied to a great variety of crops, is justified. If this period can not be observed, persons working in sprayed areas must be warned of the risk and at least provided with protective gloves. Regulations must require posted signs at reasonable intervals along the periphery of treated fields or orchards. The signs must warn against premature entry and state the date, prior to which, entry is illegal.

VI. CONCLUSIONS Reentry intoxication may occur when workers enter previously treated fields for further cultivation and harvesting. The reentry interval is the time needed for pesticides on plants to degrade to a no effect level. The methodology of determining such periods includes different approaches, the principals being: the disappearance rate of fruit and leaf surface residues, dermal exposure, and dermal dose — the cholinesterase response curve on humans or experimental animals. Reentry periods are difficult to establish and implement because of the complexity of pest control technology and changing climatic conditions. Nevertheless, research in this field is justified because of the large population entering treated fields.

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Human Toxicology of Pesticides

REFERENCES 1. Kaloyanova-Simeonova, F., Prevention of intoxication by pesticides in Bulgaria, W h ith e r R u r a l M e d ic in e Proc. 4th Int. Congr. Rural Med., Usuda (Tokoyo, 1970, 35-37. 2. Griffith, J. and Duncan, R. C., Grower reported pesticide poisonings among Florida citrus fieldworkers, J . E n v iro n . S c i. H e a lth , B. 20, 1, 61, 1985. 3. Munn, S., Keefe, T. J., and Savage, E. P., Comparative study of pesticide exposures in adult and youth migrant field workers, A rc h . E n v iro n . H e a lth , 215, 40, 4, 1984. 4. Kaloyanova, F., P e s tic id e s . T o x ic A c tio n a n d P r o p h y la x is , Bulgarian Academy of Science, Sofia, 1977. 5. Spear, R. C., Jenkins, D. L., and Milby, T* H., Pesticide residues and field workers, E n v iro n . S c i. T e c h n o l., 9, 4, 308, 1975. 6. McClure, C. D., Public health concerns in the exposure of grape pickers to high pesticide residues in Madera County, Calif., Public Health Report, September, 1976. 7. Peoples, S. A. and Maddy, K. T., Organophosphate pesticide poisoning, W est. J . M e d ., 129, 4, 273, 1978. 8. Popendorf, W., Spear, R., Leifingwell, J., Yager, J., and Kahn, E., Harvester exposure to zolone (Phozalone) residues in peach orchards,/. O c c u p . M e d ., 21, 3, 189, 1979. 9. Kundiev, J. I., Nikitin, D. P., and Hoholkova, G. A., New hygienic problems related to large use of chemicals in agriculture, G ig . S a n it., 10, 6, 1975 (in Russian). 10. Klissenko, M. A., Viotenko, I. G., and Kisseleva, N., Toxicological and chemical investigations on volatile compounds forming in the soil containing polychlorpinen and mineral fertilizers, G ig . Tr. P r o f. Z a b o L , 10, 32, 1977 (in Russian). 11. Gromov, V. L. and Gromova, V. S., Effect of pesticides on the working conditions in the weeding of sugar beet plantations, G ig . T r. P r o f. Z a b o l., 11, 43, 1977, (in Russian). 12. Van den Oever, R., Roosels, D., and Lahaye, D., Acute hazard of methyl bromide fumigation in soil desinfection, B r. J. In d . M e d ., 39, 140, 1980. 13. Izmirova, N., Benchev, I., Kaloyanova, F., Kostova, S., and Angelova, R., Determination of minimum reentry intervals after tobacco spraying by sayfos, 5th Int. Congr. of Rural Med., Varna, (Abstracts), 1972,122. 14. Izmirova, N., Benchev, I., Velichkova, V., Kaloyanova, F., Lambreva, E., Russeva, P., Kostova, E., Angelova, R., Inkova, M., Boj inova, L., Maximova, F., and Tsvetkova, P., Determination of minimal reentry intervals after tobacco and cotton treatment by organophosphorous pesticides, G ig . P r im e n . T o k s ik o l. P e s tits . K lin . O tr a v le n ii, 181, 1973, (in Russian). 15. Izmirova, N., Kaloyanova, F., Kalinova, G., and Simeonov, P., New approach to hygienic standardization of pesticides, P r o b l. H ig ., 13, 98, 1988. 16. Gutrie, F., Domanski, J., Main, A., Sanders, D., and Monroe, R., Use of mice for initial approximation of reentry intervals into pesticide treated fields, A rc h . E n v iro n . C o n ta m . T o x ic., 2, 3, 233, 1974. 17. Kraus, J. F., Mull, R., Kurtz, P., Winterlin, W., Franti, C. E., Kilgore, W., and Borhani, N. O., Monitoring of grape harvesters for evidence of cholinesterase inhibition, J . T o x ic o l. E n v iro n . H e a lth , 7, 1, 19, 1981. 18. Spear, R., Popendorf, W., Leftingwell, J., Milby, T., Davies, J., and Spencer, W., Field workers response to weathered residues of parathion,/. O c c u p . M e d ., 19, 6, 1977. 19. Popendorf, W. J. and Leftingwell, J., Regulating OP pesticide residues for farmworker protection, R e s id u e R e v ., 82, 125, 1982. 20. Popendorf, W. J., Advances in the unified field model for reentry hazards, in Proc. Symp. on Risk Assessment of Agricultural Field Workers Due to Pesticide Dermal Exposure, American Chem. Society, 1985, 323. 2 1. Nigg, H. N., Albrige, H. E., Nordby, H. E., and Stamper, J. H., A method for estimating leaf compartmentalization of pesticides in citrus, J . A g r ic . F o o d C h e m ., 29, 750, 1981. 22. Nigg, H. N. and Stamper, J. H., Considerations in worker reentry, AGS: Symposium Series No. 182, Pesticide residues and exposure, Plimmer, J. K., Ed., 1982, 59. 23. Nigg, H. N. and Stamper, J. H., Field studies: Methods overview, Proc. Symp. on Risk Assessment of Agricultural Field Workers Due to Pesticide Dermal Exposure, American Chem. Society, 1985, 95. 24. Nigg, H. N., Stamper, J. H., and Queen, R. M., The development and use of a universal model to predict three crop harvester pesticide exposure, A m e r. In d . H y g . A s s o c . J ., 45, 3, 182, 1984. 25. Kahn, E., Outlines of guide for performance of field studies to establish reentry intervals for organophosphate pesticides, R e s id u e s R e v ., 70, 27, 1979. 26. Skinner, C. S. and Kligore, W. W., Application of a dermal self-exposure model to worker reentry, J . T o x ico l. E n v iro n . H e a lth , 9, 3, 461, 1982. 27. Hugg, H., Prediction of agricultural worker safety reentry times for organophosphate insecticides, Aw. In d. H y g . A s s o c . J ., 41, 340, 1980. 28. Spinu, E. I., Bolotnyj, A. V., Zoreva, T. D., and Ivanova, L. N., Determining safe waiting times prior to entry into zones treated with pesticides, G ig . S a n it., 11,61, 1980. 29. Milby, T. H., Ed., Occupational exposure to pesticides, January 1974, Federal Working Group on Pest Management, Washington, D.C., 1974.

Reentry Periods

187

30. Nigg, H. N., Prediction of agricultural worker safety reentry times for organophosphate insecticides, A m . In d . H y g . A s s o c . J ., 41, 5, 340, 1980. 3 1. Wicker, G. W. and Guthrie, F. E., Worker crop contact analysis as a means of evaluating reentry hazards, B u ll. E n v iro n . C o n ta m . T o x ic o l., 24, 1, 161, 1980. 32. Stamper, S. H., Nigg, H. N., and Winterir, W., Growth and dissipation of pesticide oxon, B u ll. E n v iro n . C o n ta m . T o x ic o l., 27, 512, 1981. 33. Spear, R. W., Popendorf, W., Spencer, W., and Malby, T., Worker poisoning due to paraoxon residues, J . O c c u p .M e d ., 19, 6,411, 1977. 34. Iwata, Y., Knaak, J. B., Carman, G. E., Diisch, M. E., and Gunther, F. A., Fruit residue data and worker reentry research for chlorthiophos, applied to California citrus, trees, J . A g r ic . F o o d C h e m ., 30, 215, 1982. 35. Nigg, H. N. and Stamper, J. H., Dislodgeable residues of chlorbenzilate in Florida citrus: worker reentry implications, C h e m o s p h e r a , 13, 10, 1143, 1984. 36. Nigg, H. N. and Stamper, J. H., Comparative disappearance of dioxathion, malathion, oxydemeton methyl and dialifor from Florida Citrus Leaf and Fruit Services, A rc h . E n v iro n . C o n ta m . T o x ic o l., 10, 497, 1981. 37. Nigg, H. N., Reiner, J. A., Stamper, J. H., and Fitzpatrick, G. E., Disappearance of acephate methamidophos and malathion from citrus foliage, B u ll. E n v iro n . C o n ta m . T o x ic o l., 26, 267, 1981. 38. Zweig, G., LefTingwell, J. T., and Popendorf, W., The relationship between dermal pesticide exposure by fruit harvesters and dislodgeable foliar residues, J . E n v iro n . S c i. H e a lth , B ., 20, 1, 27, 1985. 39. Zweig, G., Gao, R., and Popendorf, W., Simultaneous dermal exposure to captan and benomyl by strawberry harvesters, J. A g r ic . F o o d C h e m ., 31, 1109, 1983. 40. Zweig, G., Gao, R., Witt, J. M., Popendorf, W., and Bogen, K., Dermal exposure to carbary 1by strawberry harvesters,/. A g r ic . F o o d C h e m ., 32, 1232, 1984. 41. Popendorf, W. J. and Leffingwell, J. T., Natural variation in the decay and oxidation of parathion foliar residues, J . A g r ic . F o o d C h e m ., 26, 2, 437, 1978. 42. Popendorf, W., Exploring citrus harvesters exposure to pesticide contaminated foliar dust, A m . In d . H y g . A s s o c . J ., 41,652, 1980. 43. Spear, R. C., Lee, Y. S., Leffingwell, J. T., and Jenkins, D., Conversion of parathion to paraoxon in foliar residues: effect of dust level and ozone concentrations, J . A g r ic . F o o d C h e m ., 26, 2, 434, 1978. 44. Winterlin, W. L., Kilgore, W. W., Mourer, C. R., and Sarah, R. S., Worker reentry study for captan applied to strawberries in California, J . A g r ic . F o o d C h e m ., 32, 664, 1984. 45. Winterlin, W. L., Kilgore, W. W., Mourer, R., Hall, J., and Hadapp, D., Worker reentry into captan-treated grape fields in California, A rc h . E n v iro n . C o n ta m . T o x ic o l., 15, 3, 301, 1986. 46. Batista, G. C., Stamper, J. H., Nigg, H. N., and Knapp, J. I., Dislodgeable residues of carbophenothion in Florida citrus: implications for safe worker reentry, B u ll E n v iro n . C o n ta m . T o x ic o l., 35, 213, 1983. 47. Staiff, D. C., Davies, J. E., and Robbins, I. L., Parathion residues on apple and peach foliage as affected by the presence of the fungicides maneb and zineb, B u ll. E n v iro n . C o n ta m . T o x ic o l., 17, 3, 253, 1977. 48. Iwata, Y., Knaak, J. B., Diisch, M. E., O’Neal, J. R., and Pappae, J. L., Worker reentry research for carbosulfan, applied to California citrus trees, J. A g r ic . F o o d C h e m ., 31, 1131, 1982. 49. Nigg, H. N., Stamper, J. H., Knaak, J. B., Leaf, fruit and soil surface residues of carbosulfan and its metabolites in Florida citrus groves, J. A g r ic . F o o d C h e m ., 32, 80, 1984. 50. Mestres, R., Francois, Causse, C., Vian, L., and Winnett, G., Survey of exposure to pesticides in greenhouses, B u ll. E n v iro n . C o n ta m . T o x ic o l., 35, 6, 750, 1985. 51. Kaloyanova, F. and Izmirova, N., Prevention in pesticide application in M a n u a l o f S a fe U se o f P e s tic id e s , Kaloyanova, F., Ed., Medicina i Fizkultura, Sofia, 1985, 7 (in Bulgarian). 52. Kaloyanova-Simeonova, F., Izmirova-Mosheva, N., Determination of minimum periods for safe work following spraying with organophosphate pesticides, in 1 U P A C P e s tic id e C h e m is tr y . H u m a n W e lfa re a n d th e E n v iro n m e n t, Pergamon Press, Oxford, 1983, 237. 53. Kalinova, T. N., Determination of Minimal Reentry Intervals for Safe Work with Some Organophosphate and Carbamate Pesticides, Ph.D. thesis, Sofia, 1987. 54. Federal Register, 1975, 40, 26900-26901. 55. U.S. Environmental Protection Agency, Unpublished proposed regulations, 1981. 56. Knaak, J. B., Minimizing occupational exposure to pesticides: techniques for establishing safe levels of foliar residues, R e s id u e R e v ., 75, 81, 1980. 57. Culver, B. D., Worker reentry safety. VI. O c c u p a tio n a l H e a lth A s p e c ts o f E x p o s u r e to P e s tic id e R e s id u e s , Springer-Verlag, New York, 1976, 41.

INDEX A

Asulam, 44 Axothoate, 4 Azinphos ethyl, 4 Azinphos methyl (gluthion), 4, 181 combined pesticide exposure, 163 dose-effect relationship, 8 permissible levels, 32 monitoring exposure, 23, 24, 25 reentry intoxications, 184 Azocyclotin, 112 Azodrin, 175

Abate dose-effect relationship, 8 permissible levels, 32 Acephate, 182 Acephatex, 182 Acetophos methyl, 32 Acrex, 132 Actelik, 185 Acute intoxication, epidemiology of, 173-179 Acylate, 54 Afugan, 32 Agent Orange, 142 Aldicarb, 44 acute intoxication, 47 epidemiology of acute intoxication, 176 mechanisms of action, 46 metabolism, 43, 45 permissible levels, 53 volunteer studies, 48 Aldoxycarb, 43 Aldrin, 59 acute intoxication, 77 carcinogenicity, 65 chronic effects, 86-89 LDS0,63 levels in workers, 76, 77 percutaneous penetration, 60 permissible levels, 90, 91 physical properties, 62 protein binding, 65 structure, 61 Alkylcarbamates, occupational exposure, 50 Alkylcarbamyls, ChE reactivation time, 45 Alky lmercury compounds, 117-122 Alkylparathion, reentry intoxications, 184 Alkylphenylcarbamates, 54 Alkyl-thiophanate, 53 Alkyltin compounds, see Organotin compounds Allethrin, 102, 103, 105 Allethroline, 101 Allycinerin, 102 Allylxycarb, 43 Alphamethrin, 101, 103 Ambush, 102 Ambushfog, 102 Amidithion, 4 Amidophos, 32 Aminocarb, 43 mechanisms of action, 46 metabolism, 43 permissible levels, 53 Amiton, 4 Amitrol, 163 Antagonisms, combined pesticide exposure, 161 Anthio, 21, 32 Antipyrin, 81 Aquacide (diquat), see Dipyridiliums Aquatin (triphenyltin chloride), 112 Aremo, 103 Arseniacals, 174

B Baricard, 103 Bastox, 103 Basudin, 32 Bavistin (carbendazim), 131, 132 Baygon, see Propoxur Baytex, 32 2,4-B [(2,4-dichlorophenoxy)butyric acid], 136 Belmark, 103 Bendiocarb, 43 metabolites, 45 permissible levels, 53 Benlate, see Benomyl Benomyl, 131, 132 combined pesticide exposure, 163 exposure, 46 permissible levels, 53, 54 reentry intoxications, 183 structure, 44 Benzene hexachloride (BHC), 59, 161 chronic effects, 79 epidemiology of acute intoxication, 177 tissue concentrations, 71 blood and urine, 72 fat tissue, 67-69 fetal tissues and newborns, 73 pregnant women, 70, 74 Benzimidazole compounds, 44, 54, 131-133 Benzofuroline, 102 Betamal, 54 Betonal (fendifam), 54 Bidrin, 22 Bioallethrin, 101 Biobenzylfuroline, 102 /7-Biomophenoxy triethyl tin, 113 Biopermethrin, 102 Bioresmethrin, 102, 103 Bipyridiliums, 177 BPMC, 43 Bretdan (fentin acetate), 112 Bromophos, 4 dose-effect relationship, 8, 9 permissible levels, 32, 33 Bromophos ethyl, 4 Bromoxyl, 161 Bromoxynil, 160 Bufencarb, 43 Butacarb, 43 Butontate, 5

189

190

Human Toxicology of Pesticides C

Camphechlor, 87 Captan combined pesticide exposure, 163 reentry intoxications, 183, 184 Carbamates, 43-55, 131, 132 combined pesticide exposure, 163, 166 epidemiology of acute intoxication, 174, 175 exposure, 46-51 biological indicators, 50-53 dose-effect relationships, 51 long-term, 50 occupational, 48-50 short-term, 48-50 volunteer studies, 47,48 mechanisms of action, 44-46 metabolism, 43, 44 occupational exposure, 50 prevention, 53, 54 properties, 43, 44 reentry intoxications, 184 treatment, 53 use, 43 Carbamyl, 45 Carbanolate, 43 Carbaphenthion, 184 Carbary 1 acute intoxication, 47 exposure, 46, 47 metabolism, 43^15 occupational exposure, 49, 50 permissible levels, 53, 54 reentry intoxications, 183 structure, 44 volunteer studies, 47 Carbendazim, 44, 53, 131, 132 Carbin, 54 Carbofuran, 44 acute intoxication, 47 metabolites, 45 occupational exposure, 48 permissible levels, 53, 54 reentry intoxications, 184 Carbophos, 32 Carbosulfan, 184 Chismethrin, 102 Chlorbufam, 44 Chlordane, 59 carcinogenicity, 65 chronic effects, 87, 88 combined pesticide exposure, 162 drug interactions, 63, 64 exposure, 66 LDW,63 permissible levels, 90, 91 physical properties, 62 structure, 61 Chlordecone, 81, 82 Chlorfenvinphos, 4 Chlorinated terpenes, LDS0, 63 Chlor IPC, 54 Chlorobenzylate, 59, 63 Chlorocyanide, 181 4-Chloro-2-methyl phenoxyacetic acid, see MCPA 4-Chloro-2-methyl phenoxybutyric acid (MCBA), 136

a-(4-Chloro-2-methyl phenoxy)propionic acid (MCPP), 136 Chlorophenothane, 61 Chlorophos, 7, 9, see also Trichlorfon chronic intoxication, 13 combined pesticide exposure, 162, 165 effects, 22 permissible levels, 32 Chlorothion, 28 Chlorphanate methyl, 132 Chlorphenoxy compounds, 135-145 effects, 139-143 exposure, 137-139 metabolism, 135, 137 modes of action, 137 properties, 135 safe levels, 143, 144 structure, 136, 137 uses, 135 Chlorphenesin, 59 Chlorpyrifos, 4 cholinesterase inhibition, 27 dose-effect relationship, 8 neuropathy, delayed, 15 permissible levels, 33 Chlorpyrifos methyl, 4, 33 Chlorthiophos, 184 Chrysanthemic acid esters, 101, see also Pyrethroids Chryson, 102 Cinerolone, 101 Cloethocarb, 44 Combined effects of pesticides, 161-169 hematopoietic system, 166 immune system, 164-166 long-term, 168, 169 nervous system, 166-168 respiratory system, 162, 163 vision, 167, 168 Coopex, 102 Copper compounds, 162, 166 Corsair, 102 Coumaphos, 4, 33 Crotoxyphos, 4 Cruformate, 4 Cyanides, 181 Cyanofenphos, 5 Cyanox contact dermatitis, 11 permissible levels, 32 Cyhalothrin, 101, 103, 104, 107 Cymbush, 103 Cyperkill, 103 Cypermethrin, 103-105, 107

D 2,4-D (2,4-Dichlorphenoxyaceticacid), 135, 136 dose-effect relationship, 143 effects, 139, 140 effects, occupational exposure, 140-142 exposure, 139 properties, 137 safe levels, 143, 144 Danitol, 103 DCPA, 135, 136 DDA, 72

Index DDD, 71 DDE epidemiology of acute intoxication, 173 tissue concentrations, 70, 71 fat tissue, 67-69 human milk, 74 DDT, 3, 59 acute intoxication, 78 biotransformation, 60 chronic effects, 78-84 combined pesticide exposure, 162, 164, 165, 168 drug interactions, 64 environmental levels, 60 epidemiology of acute intoxication, 173, 177 exposure, 65 LDW,63 levels in workers, 75-77 multiple-pesticide exposure, 161 permissible levels, 90, 91 physical properties, 62 and pregnancy, 70, 73, 74 structure, 61 tissue concentrations, 71 blood and urine, 70, 72 fat, 66-70 fetal tissues and newborns, 73 human milk, 73, 74 pregnant women, 70, 73, 74 DDVP, 22 contact dermatitis, 11 dose-effect relationship, 9 permissible levels, 32 Decamethrin, 103, 107 Decasol, 103 Decis, 103, 132 DEF, 15 Deldrin, 59 Deltamethrin, 103- 107, 184 Demeton cholinesterase inhibition, 27 permissible levels, 32, 33 Demeton-S-methyl, 4, 8 Derosal (carbendazim), 131, 132 Desmedipham, 44 Dextront (paraquat), see Dipyridiliums Dialifor, 181, 182 Dianisyl trichloroethane, 61 Diazinon, 4 cholinesterase inhibition, 27 combined pesticide exposure, 162 contact dermatitis, 11 dose-effect relationship, 8 effects, 22, 23 monitoring exposure, 26 neurobehavioral effects, 17 permissible levels, 32, 33 Dibrom, 32 Dibutyltin dialurate tetraisobutyltin, 113 Dicamba, 138, 139 Dichlorfenthion, 4, 12 Dichlorobenzol, 168 Dichlorodiphenyl trichloroethane, 61 Dichloroethane, 79 (2,4-Dichlorophenoxy)butyric acid (2,4-B), 136 Dichloroprop[2(2,4-Dichlorophenoxy)propionic acid (2,4-DP)], 136, 138, 139, 143, 144

191

2,4-Dichlorphenoxyacetic acid (2,4-D), see 2,4-D Dichlorphos, 4, 8 combined pesticide exposure, 162 dose-effect relationship, 9 effects, 21 reentry intoxications, 185 Dichlorvos, 117 cholinesterase inhibition, 27 epidemiology of acute intoxication, 177 permissible levels, 32 Dichrotophos, 31 Dicophane, 61 Dicotex (4-Chloro-2-methyl phenoxyacetic acid), 136 Dicrotophos, 4, 31, 32 Dieldrin acute intoxication, 77 carcinogenicity, 65 chronic effects, 82, 86-89 drug interactions, 64 levels in workers, 76, 77 percutaneous penetration, 60 permissible levels, 90, 91 protein binding, 65 tissue concentrations in general population, 71 blood and urine, 72 fat tissue, 67-70 fetal tissues and newborns, 73 human milk, 73 pregnant women, 74 Diethyl phosphate (DEP), 29, 184 Diethyl phosphodithionate (DEDTP), 29 Diethylthiophosphate (DETP), 17, 184 Difocol, 184 Dimefox, 27 Dimethalan, 44 Dimethoate dose-effect relationship, 8 reentry intoxications, 185 Dimethylan, 43 Dimethylcarbamyl, 45 Dimethyl phosphate (DMP), 29, 161 Dimethyl phosphodithionate, 29 Dimethyl phosphothionate (DDETP), 29 Dimetoate, 4 Dinitrobutylphenol, 160 Dinitroorthocresol (DNOC), 160, 161 Dinitrophenyl, 132 Diocation, 181 Dioxacarb, 44 Dioxane, 181 Dioxanthin, 8 Dioxathion, 4, 182 Dipterex, see also Chlorphos; Trichlorfon dose-effect relationship, 7, 9 effects, 22 Dipyridiliums, 147-156 effects, 149-155 concentrations in biological fluids, 154, 155 kidney, liver and gastronitestinal system, 152, 153 lung damage, 150-152 oral intoxication, 149, 150 skin, 153, 154 skin, 153, 154 exposure, 148, 149 metabolism, 148

192

Human Toxicology of Pesticides

prevention, 156 properties, 144 recovery, 156 toxicity, 148 treatment, 155 uses, 144 Diquat, 163, see also Dipyridiliums Disulfotan, 4, 8 Dithiocarbamates, 125-129, 132, 163 2,4-DP, see Dichloroprop [2(2,4-Dichloro-phenoxy)propionic acid] Dragnet, 102 Dursban, 26 Duter phenostat H, 112

E Eksmin, 102 Endosulfane, 59 Endrin, 59 acute intoxication, 77 chronic effects, 86-89 epidemiology of acute intoxication, 173 in fat tissue, 69 LD50,63 permissible levels, 90 Epidemiology of acute intoxication, 173-179 EPN, 5 combined pesticide exposure, 162 neuropathy, delayed, 15 Eptam, 54 Equidazin (carbendazim), 131, 132 Esbiol, 102 Esgram (paraquat), see Dipyridiliums Ethiofencarb, 53 Ethion, 4, 33 Ethuifencarb, 44 Ethylbromophos, 33 Ethylparathion, 25, 184 Ethylsulfonate, 79, 80 Etion, 181 Etrimphos, 33 Exbrothrin, 102

F Fastak, 103 Fenamiphos, 4, 32, 33 Fenbutantin oxide, 111, 112 Fenchlorophos, 4 dose-effect relationship, 8 permissible levels, 33 Fenitrothion (simithion), 4 contact dermatitis, 11 dose-effect relationship, 9 permissible levels, 33 Fenopathrin, 103, 105 Fensulfothion, 4, 32, 33 Fenthion, 4, 32, 33 Fentin acetate, 112 Fenvalerate, 103-107 Ferbam, 125, 126, 128 Flucythrinate, 107 Formethanate, 44 Formothion, 4 dose-effect relationship, 8 permissible levels, 33

Fosdrin, 185 Fosthietan, 4 Fundazol (benomyl), 131, 132, see also Benomyl

G Gluthion, see Azinphos methyl Gramoxone (paraquat), see Dipyridiliums Grenade, 103 Gusathion, 174 Gusathion methyl, 175

H Halogenated hydroxybenzonitrile, 160 Heptachlor, 59 carcinogenicity, 65 drug interactions, 64 exposure, 66 LD50,63 permissible levels, 90, 91 physical properties, 62 structure, 61 Heptachlor epoxide, 82 in fat tissue, 66, 67 tissue concentrations in general population, 71 fetal tissues and newborns, 73 human milk, 73 pregnant women, 74 Heptenphos, 4 Hexachloran, 3 chronic effects, 78-80, 85 reentry intoxications, 181 Hexachlorobenzene (HCB), 173 chronic effects, 88, 89 epidemiology of acute intoxication, 173 exposure, 65, 66 levels in workers, 75, 76 permissible levels, 90, 91 physical properties, 62 protein binding, 65 structure, 61 treatment, 89, 90 Hexachlorobutadiene, 78, 79 Hexachlorocyclohexane (HCH), 59 chronic effects, 84, 85 in human milk, 74 permissible levels, 90 Hoppicide, 44 Hospmet, 4 Hydrogen cyanide, 181

I IDEF, 14 Intrathion, 185 Iodofenphos, 4, 32 Ioxynil, 160 IPS (Isopropyl-A-phenylcarbamate), 54 Isathrin, 102 Isodrin, 59 Isofenphos, 3, 33 Isoprocarb, 44 Isopropyl-A-phenylcarbamate (IPS), 54

j Jasmolone, 101

Index K Kafil, 102 Karate, 103 Katalon (paraquat), see Dipyridiliums Kelthane, 59, 63 Kilval, 11,32 Kothrin, 103

L Lanate, 174 Landrin, 43 Lannate, 174, 175 Leptophos, 5, 11 epidemiology of acute intoxication, 174 neuropathy, delayed, 15 Lindane, 82 acute intoxication, 78 chronic effects, 85, 86 exposure, 65 in fat tissue, 67-69 LD50,63 percutaneous penetration, 60 permissible levels, 90, 91 physical properties, 62 structure, 61

M M -81 (0 ,0 -dimethyl-S-ethylmercatproethyl-dithiophosphate), 82 Malathion, 4 acute nitoxication, 12 cholinesterase inhibition, 27 combined pesticide exposure, 162 contact dermatitis, 11 dose-effect relationship, 8, 9 effects, 21 entry routes, 9 epidemiology of acute intoxication, 176 metabolism, 3-7 neuropathy, delayed, 16 neurotoxicity, 14 permissible levels, 32, 33 reentry intoxications, 182 Maneb, 125-128 MCBA (4-Chloro-2-methyl phenoxybutyric acid), 136 MCPA (4-chloro-2-methyl phenoxyacetic acid), 136 effects, 139, 140 exposure, 138, 139 MCPA (4-chloro-2-methyl phenoxyacetic acid), 136 MCPP [a-4-Chloro-2-methyl phenoxy) propionic acid], 136 Mecarbam, 4 Mecoprop [a-4-Chloro-2-methyl phenoxy) propionic acid], 136 Menazone, 4 Meothrin, 103 Merbate, 48 Mercaptophos, 13 Mercury compounds, 117-122 Merphos, 14-16 Metacrifos, 33 Metam dosium (vapam), 125, 126 Metamidophos, see Tamaron Metasistox, 20, 21

Methafos, 32 Methamidofos, 4 neuropathy, delayed, 15 permissible levels, 33 reentry intoxications, 182 Methamyl, 46 Methidothion, 4 dose-effect relationship, 8 permissible levels, 33 Methiocarb, 44 mechanisms of action, 46 permissible levels, 53 reentry intoxications, 183 Methomyl, 44 Methoxychlor, 59 LD,„,63 permissible levels, 91 physical properties, 62 structure, 61 Methyl-2-benzimidazole carbamate, 131 Methylbromide, 174 Methylcarbamyl, 45 Methyldemeton, 23 Methylethylphos, 13 Methylmercaptophos (sistox), 20, 21, 32 Methyltin, 111 Methyl topsin (thiophanate methyl), 131, 132 Metrifonate, 24 Mevinphos, 4 cholinesterase inhibition, 27 combined effects, 162 dose-effect relationship, 8 effects, 22 EMG findings, 16 monitoring exposure, 23 permissible levels, 32, 33 Mexacarbate, 44, 47 Mipaphox, 15, 27 Mirex, 68 Monocrotophos, 4, 32, 33 Morphothion, 4

N Nabam, 125, 126 Naled, 4, 32 Necarboxyl acid, 102 Neopynamin, 102 Nicotine, 174, 175 Nitrophenols combined pesticide exposure, 166 epidemiology of acute intoxication, 174 Nitrosocarbaryl, 54 Nizole, 160

o Obidoxime, 31 Octachlor, 61 Octamethyl, 32 Omethoate, 4 neurotoxicity, 14, 16 permissible levels, 33 op'DDD, 64 Organochlorine compounds acute effects, 77, 78

193

194

Human Toxicology of Pesticides

combined pesticide exposure, 161-163, 165-168 chronic effects, 78-89 cyclodienes, 86-89 DDT, 82-84 HCH, 85, 86 lindane, 85, 86 epidemiology of acute intoxication, 174, 175, 177 metabolism, 59, 60, 63 occupational exposures, 75-77 pathology, 74, 75 prevention, 90, 91 properties, 59, 61, 62 structure, 61 tissue levels, 66-74 body fluids, 70, 72 fat, 66-70 in pregnancy, 70, 73-74 toxicity, 60, 63-65 treatment, 89, 90 use, 59 Organomercurial compounds, 117-122 combined pesticide exposure, 165, 166 epidemiology of acute intoxication, 174, 176 Organophosphate compounds, 3-33 biological monitoring, 23-26 combined pesticide exposure, 161-166, 168 common names, 4, 5 dose-effect relationships, 7-10 epidemiology of acute intoxication, 174, 175, 177 exposure indicators, 26-30 in blood, 29 cholinesterase activity, 26-28 electromyography, 29, 30 lymphocyte NTE, 30 in urine, 28 individual compounds, effects of, 19-23 long-term effects, 19 metabolism, 3, 5 nervous system effects behavioral effects, 17 CNS, 17 delayed neuropathy, 14-16 EEG, 18, 19 electromyography, 16, 17 eyes and vision, 19 neurotoxicity, 14-16 occupational exposures, 7, 9, 10 permissible exposure levels, 31-33 prevention, 31-33 properties, 3-5 reentry intoxications, 181-183, 185 structure, 4, 5 toxicity, MOA, 5-7 treatment, 30, 31 uses, 3 Organosulfur compounds, 165 Orvar (paraquat), see Dipyridiliums Osadan (fenbutatin oxide), 112 Outflank, 102 Oxamyl, 44 metabolites, 45 in permissible levels, 53

Oxanyl, 160 Oxon, 182 Oxydemeton methyl, 4, 182

P Pallethrin, 102 Paranitrophenol, 20 Paraoxon,181,182 Paraquat, see also Dipyridiliums combined pesticide exposure, 163 epidemiology of acute intoxication, 177 Parathion, 4 acute intoxication, effects of, 10, 11 adapatation toward, 19, 20 cholinesterase inhibition, 27 combined pesticide exposure, 161-163 dose-effect relationship, 8, 9 effects, 19,20, 22 entry routes, 9 epidemiology of acute intoxication, 173, 177 metabolism, 3-7 monitoring exposure, 23-26, 28 neuropathy, delayed, 16 neurotoxicity, 14 permissible levels, 32 reentry inntoxications, 181 reentry intoxications, 183, 184 Parathion methyl, 4 cholinesterase inhibition, 27 chronic intoxication, 13 epidemiology of acute intoxication, 175, 177 monitoring exposure, 23, 25 permissible levels, 32, 33 reentry intoxications, 184, 185 PCBs, 74 Pentachlorophenol (PCP) combined pesticide exposure, 161, 168 toxicokinetics, 60 Peregrin, 102 Perepal, 112 Permasect, 102 Permethrin, 102-107 Pesgard, 102 Pethrin, 102 Phenitrothion, 8 Phenmedipham, 44 Phenol nitro derivatives, combined pesticide exposure, 166 Phenostat C (triphenyltin chloride), 112 d-Phenothrin, 102-105, 107 3-Phenoxybenzyl alcohol, 101 Phenthion, 8 Phentoate, 4, 33 Phenylcarbamates, alkyl, 54 Phloxim, 4 Phorate, 4 Phosalone, 4, 181 entry routes, 9 permissible levels, 32, 33 reentry periods, 181 Phosdrin, see also Mevinphos

Index combined pesticide exposure, 162 effects, 22 Phosfolan, 9 Phosgen, 181 Phosmet, 33 Phosphamide, 32 Phosphamidon, 4, 33 Phosvel, 11, 15, see also Leptophos Phoxim,4 Phthalophos, 32 Phthalthrin, 102 Picket, 102 Picloram, 139 Pictran, 113 Pirimicarb, 44 Polychlopinen, 79 Polychlorocamphen, 59, 87 Polychlorpinenes, 59, 78, 79, 88, 181 Potentiation, combined pesticide exposure, 161 Pounce, 102 Pramex, 102 Primicarb, 53 Primiphos methyl, 4 Primor, 185 Profenofos, 4 Promacyl, 44 Promecarb, 44,45 Propoxur dose-effect relationship, 51 indicators of exposure, 51, 52 mechanisms of action, 45 metabolism, 43— 45 occupational exposure, 48, 49 permissible levels, 53, 54 volunteer studies, 47 Prothiofos, 4 Prothoate, 4 Pynamin, 102 Pynosect, 102 Pyrasophos, 4 Pyrdin, 103 Pyresin, 102 Pyrethric acid esters, 101, see also Pyrethroids Pyrethroids, 101-108, 132 effects, 105-107 exposure, 104, 105 metabolism, 101, 102 mode of action, 102, 104 prevention, 107 properties, 101, 102 uses, 101 Pyrethrolone, 101 Pyrimiphosmethyl, 8 Pyrimor, 54

R Reentry intoxication, 181-184 Reglone (diquat), see Dipyridiliums Reglox (diquat), see Dipyridiliums Resmethrin, 102, 103, 105 Ripcord, 103

195

s Salithion, 11 Sayfos, 32, 185 Sevin, 52 epidemiology of acute intoxication, 175 occupational exposure, 50 Seythe (paraquat), see Dipyridiliums Shradan, 9 Simazine, 160, 161 Simithion, see Fenitrothion Sistox, 20, 21, 32 Sodium trichloracetate, 181 Stockard, 102 Stomexin, 102 Sulfotep, 4 Sulfur compounds combined pesticide exposure, 165 epidemiology of acute intoxication, 175 Sulphrofos, 4 Sumicidin, 103 Supersect, 103 Symethrin, 102 Synthrin, 102

T 2,4,5-T (2,4,5-Trichlorophenoxyacetic acid), 136 dose-effect relationship, 143 effects, 139, 140 effects, occupational exposure, 140-142 exposure, 137-139 properties, 137 Talcord, 102 Tamaron (methamidofos), 4, 33 epidemiology of acute intoxication, 174 reentry intoxications, 185 TCDD(2,3,7,8-tetrachlorodobenzo-/?-dioxin), 135,136, 141, 144 Temephos, 4 Temik, see Aldicarb TEPP, 4 Terbufos, 9 Tetrachlorvinphos, 4 Tetrahydrophthalimide (THPI), 184 Tetramethrin, 102, 103 Tetramethyl thiramdisulfide (TTD), 125, 128, 165 Thimeton, 4 Thiodan, 63, 177 Thiodicarb, 44 Thiofonax, 44 Thionazin, 4 Thiophanate, 33, 66 Thiophanate ethyl, 44 Thiophanate methyl, 44, 53, 131, 132 Thiuram (TMTD), 127, 128 Tin compounds, see Organotin compounds Tinnate (triphenyltin chloride), 112 Torgue (fenbutatin oxide), 112 Tornado, 102 Tortil, 161 Toxaphene, 87 acute intoxication, 77

196

Human Toxicology of Pesticides

combined pesticide exposure, 164 LD[50], 63 Toxic gas generation, 181, 182 Toxinyl, 161 2,4,5-TP [2-(2,4,5-Trichlorophenoxy) propionic acid], 136 Trialkyltin compounds, see Organotin compounds Triamifos, 4 Triazine, 160 Triazophos, 4, 33 Tributyltin compounds, 113 Tribyton, 5 Trichlorfon, 5 Trichlormat, 5, 15 Trichloroethane, 61 Trichlorofon/trichlorophon cholinesterase inhibition, 27 dose-effect relationship, 8 effects, 22 neuropathy, delayed, 15 permissible levels, 33 Trichlorometphos, 32 2-(2,4,5-Trichlorophenoxy)propionic acid (2,4,5-TP), 136 Trichlorophor, 9 Tricyclohexyltin hydroxide, 113 Triethyltin bromide, 113 Trifenofos, 4 Trimethacarb, 44 Triphenyltin acetate triphenyl hydroxide, 113 Trivinyltin, 113 Trolen, 32 TTD (tetramethyl thiramdisulfide), 125, 128

U Unden, 131, 132, 185 V Valexon, 32 Vamidothion, 4, 33 Vapam, 125, 126 Vapona, 9 Vaponite, 26 Velsicol 1068, 61 Vendex (fenbutatin oxide), 112 Vidate, 185 Vinclosolin, 183

W Weedol (paraquat), see Dipyridiliums Weedrite (paraquat), see Dipyridiliums Weedtrim (diquat), see Dipyridiliums X XMC, 44 Xylycarb, 44 Z Zarine, 22 Zectran, 48 Zineb, 125-128, 132 Ziram, 125-128, 165 Zolon, 181